Transdermal compositions

ABSTRACT

The present invention is directed to transdermal compositions and the uses thereof. These compositions include at least one of the following components: a C 1 -C 6  dialkyl, C 12 -C 30  dialkyl quaternary ammonium salt, a C 12 -C 30  fatty acid, a nitrogenous organic base, C 12-30  fatty alcohol, monoglyceride or the reaction products thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of and claims the benefit under35 USC §120 to U.S. patent application Ser. No. 13/249,915, filed Sep.30, 2011, which is a continuation of and claims the benefit under 35 USC§120 to U.S. patent application Ser. No. 12/630,690, filed Dec. 3, 2009,now U.S. Pat. No. 8,101,163, which is a divisional of and claims thebenefit under 35 USC §120 to U.S. patent application Ser. No.10/670,034, filed Sep. 22, 2003, abandoned, which claims the benefitunder 35 USC §119(e) of U.S. Patent Application No. 60/412,437, filedSep. 20, 2002, all of which are hereby incorporated by reference hereinin their entireties.

BACKGROUND OF THE DISCLOSURE

1. Field of the Invention

The present invention is directed to compositions useful as a carrierfor transdermal compositions. These compositions are also useful, incombination with active agents, in the treatment of skin diseases, skininjuries, chronic skin conditions and the like. The transdermalcompositions of the present invention are directed to products formed bythe reaction of combinations of a quaternary ammonium salt, a fattyacid, a fatty alcohol, a nitrogenous base and a monoglyceride.

2. Background of the Prior Art

The design of a composition which, when applied in combination with anactive agent, to treat various skin diseases, skin injuries, chronicskin conditions and the like is complex due to the necessity of insuringdelivery of the active agent to the proper place on or below skin,providing proper permeation into the skin and providing the desiredphysical separation, if any, of the composition from the skin surface. Adesirable transdermal composition topically delivers medicinal activeagent or agents to the dermally affected portions of the body; providesnecessary nutrients and building block precursors; promotes normaland/or healing microbial activity at the site of the skin to be treatedyet inhibits outside infections caused by external pathogenic bacterialor viruses; and, optimally, modifies electrical charged density in andaround the portion of the skin to be treated so as to attractbiologically provided nutrients and building block precursors to thesite which may have a deficient blood supply.

The above remarks establish the difficulty of designing compositions fortransdermal use which meet all of the above requirements of an efficienttransdermal composition. However, the problem is multiplied when it isappreciated that the cost of preparing a wide range of effectivecompositions which meet all of these requirements for all skinconditions is quite imposing. That is, the requirement to meet all ofthe aforementioned requirements is a function of the skin condition tobe treated or the skin malady to be prevented. The requirements ofmeeting all of the aforementioned conditions depend on the specificcondition to be treated or prevented. Thus, a composition which meetsall of the requirements mentioned above in the case of a burnt skin maynot be effective to meet all of the requirements when a skin irritationis to be treated. In those cases totally different compositions may beutilized. Thus, the costs of providing a wide range of compositionssuitable for transdermal compositions is imposing.

The above remarks establish the need in the art for efficienttransdermal compositions that may be utilized to prepare a compositionfor transdermal utilization which can be adjusted by minor additions orsubtractions to provide a “universal transdermal composition.” It isthus apparent that there is a strong need in the art for a new class ofcompositions useful for transdermal application which meets all of therequirements for skin treatment and malady prevention without undueexpense due to the requirement for a whole plurality of differentcomponents.

BRIEF DESCRIPTION OF THE INVENTION

It has now been discovered that new classes of compositions, useful fortransdermal applications can be prepared from just a few differentcompounds if thermodynamic conditions are within certain parameters.

In accordance with the present invention transdermal compositions areprovided. These compositions include at least one or more of thefollowing components: a C₁-C₄ dialkyl, C₁₂-C₂₁ dialkyl quaternaryammonium salt, a C₁₂ to C₂₆ fatty acid, a nitrogenous organic base, aC₁₂ to C₂₆ fatty alcohol and a glycerol ester of a C₁₂ to C₂₆ fatty acidand the reaction products thereof.

In further accordance with the present invention new compounds formed byreaction of the C₁₂-C₂₆ fatty acid and the quaternary ammonium salt andthe reaction product of the fatty alcohol and the glycerol ester havebeen discovered.

In another embodiment, the present invention is further directed to newtertiary amides of the formula

or pharmaceutically acceptable salts thereof wherein

R₄ is a fatty group having 11-25 carbon atoms;

R₅ and R₆ are independently aryl, aryl lower alkyl, or fatty group of11-25 carbon atoms or R₇;

R₇ is R₁—Ar—O—R₂—R₃—;

R₁ is alkyl group containing 1-15 carbon atoms;

R₂ and R₃ are independently lower alkylene groups containing 1-6 carbonatoms and Ar is aryl.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be better understood by reference to theaccompanying drawings of which:

FIG. 1 is a plot of pH as a function of the time before addition of, andthe mass of, triethanolamine added in the reaction mixture in Example10. In the figure, the negative numbers are minutes from TEA addition,while positive numbers are minutes from TEA addition. The - representscetyl alcohol, --- represents glycerol monolaurate and - represents TEAand DDAC, which are the same amount.

FIG. 2 is a plot of pH as a function of the time from addition ofstearic acid in the reaction mixture of Example 12;

(a) the arrow at (a) points to initial pH drop;

(b) the arrow at (b) points to pH increase forming an ion pair;

(c) the arrow at (c) refers to pH decline as the amide is formed; and

(d) the arrow at (d) refers to pH increase after TEA addition.

FIG. 3 is a plot of pH as a function of triethanolamine in theneutralization of the reaction mixture of Example 13. The - indicates aphase change.

FIG. 4 is a plot of pH as a function of temperature in the formation ofthe amide hydrate.

FIG. 5 is a plot versus the mole ratio benzethonium chloride/CLA. In thefigure, the ---- represents the line where the mole ratio is 1:1 while -represents the pH. A is stage 1 of the reaction, B is stage 2, C isstage 3, D is stage 4 and E is stage 5.

DETAILED DESCRIPTION

The term “lower alkyl”, when used alone or in combination, means analkyl group containing 1-6 carbon atoms. The lower alkyl group may bebranched or straight chained. Preferred lower alkyl contains 1-4 carbonatoms and more preferably 1 or 2 carbon atoms and most preferablymethyl. Examples of lower alkyl include methyl, ethyl, propyl,isopropyl, butyl, t-butyl, isobutyl, sec-butyl, pentyl and hexyl.

As used herein, aryl, when used alone or in combination, is an aromaticgroup comprised solely of carbon ring atoms. The aryl group may bemonocyclic, bicyclic or tricyclic. If more than 1 ring is present, therings are fused; thus the aryl group also includes polynucleararomatics, i.e., bicyclic and tricyclic fused aromatic rings. The arylgroup contains 4n+2 ring carbon atoms, wherein n is 1-4. The aryl groupcontains 6, 10, 14 or 18 ring carbon atoms and up to a total of 25carbon atoms. It is preferred that n is 1-3. The preferred aryl groupsare phenyl, naphthalene, including alpha and Beta-naphthalene,anthracene, phenanthrene, and the like. The most preferred aryl group isnaphthalene, but especially phenyl.

The aryl group may be unsubstituted or substituted with one or moreelectron donating groups or electron withdrawing groups. The terms“electron withdrawing groups” and “electron donating groups” refer tothe ability of a substitutent to withdraw or donate electrons relativeto that of hydrogen if the hydrogen atom occupied the same position inthe molecule. These terms are well understood by one skilled in the artand are discussed in Advanced Organic Chemistry, by J. March, 4^(th) Ed.John Wiley and Sons, New York, N.Y. pp. 16-18 (1992), and the discussiontherein is incorporated by reference. Examples of electron withdrawinggroups include halo, especially fluoro, bromo, chloro, iodo, and thelike; nitro; carboxy; formyl; lower alkanoyl; carboxyamido;triloweralkylamino; aryl; trifluoromethyl; aryl lower alkanoyl; lowercarbalkoxy; and the like. Examples of electron donating groups includesuch groups as hydroxy; lower alkoxy, including methoxy, ethoxy, and thelike; lower alkyl; amino; lower alkylamino; dilowerlakylamino; aryloxy(such as phenoxy); mercapto; mercapto lower alkyl; lower alkylthio; andthe like. One skilled in the art will appreciate that the aforesaidsubstituents may have electron donating properties under one set ofcircumstances and electron withdrawing properties under differentchemical conditions or circumstances; these are also contemplated to bewithin the scope of these terms. Moreover, the present inventioncontemplates any combination of substituents selected from theabove-identified terms.

It is preferred that the aryl group is unsubstituted or substituted bylower alkyl groups.

The term “aryl lower alkyl group” refers to a lower alkyl group asdefined herein bridging an aryl group, as defined herein, to the mainchain. Examples include benzyl, phenethyl, phenpropyl, phenisopropyl,phenbutyl, diphenyl methyl, 1,1-diphenylethyl, 1,2-diphenylethyl, andthe like.

The fatty acid or fatty alcohol as used herein may be saturated orunsaturated aliphatic which may be straight or branched chain. It ispreferred that the fatty acid contains 12-30 carbon atoms and morepreferably 16-22 carbon atoms and most preferably 16-20 carbon atoms. Itis also preferred that the aliphatic portion of the fatty acid or fattyalcohol radical is saturated or contains 1-8 carbon-carbon double bondsand more preferably 1-6 carbon-carbon double bonds. In one embodiment,the aliphatic portion of the fatty acid or fatty alcohol contains 1, 2or 3 carbon-carbon double bonds. Examples include lauric acid, myristicacid, palmitic acid, stearic acid, behenic acid, arachidic acid, oleicacid, linoleic acid, palmitoleic acid, linolenic acid, arachidonic acidand the like.

As used herein, the term “fatty group”, when used alone or incombination is a fatty acid group without the terminal carboxy moiety onthe omega carbon of the chain.

In other words, it is R₈ wherein

is the corresponding acid. The fatty group (R₈) contains 11-29 carbonatoms and more preferably contains an odd number of carbon atoms.Preferably, it contains 15-21 carbon atoms. It may be completelysaturated or contain 1-8 carbon-carbon double bonds. It is preferredthat the fatty group is saturated or contains one to six carbon-carbondouble bonds. However, the fatty group may contain less than sixcarbon-carbon double bonds, e.g., one or two or three carbon-carbondouble bonds. It may be straight chained or branched.

The quaternary ammonium salts used in the present invention include fourgroups around the central nitrogen atom. They may include combinationsof short chain alkyl groups, containing 1-4 carbon atoms, fatty groups,aryl, and aryl lower alkyl group.

In addition, the nitrogen atom in the quaternary ammonium salts or inthe tertiary amide may be substituted by R₇ wherein R₇ isR₁—Ar—O—R₂—O—R₃—wherein R₂ and R₃ are lower alkylene groups containing 1-6 carbon atoms,R₁ is a lower alkyl group and Ar is aryl. It is preferred that R₂ and R₃contains 1-3 carbon atoms and more preferably 1 or 2 carbon atom. It isalso preferred that R₂ and R₃ are the same. It is even more preferredthat R₂ and R₃ are the same and contain 1 or 2 carbon atoms and mostespecially 2 carbon atoms.

R₁ is preferably an alkyl group containing 1-15 carbon atoms and morepreferably 1-10 carbon atoms. It may be straight chained or branched.

In the quaternary ammonium salts it is preferred that the centralnitrogen atoms is substituted by at least two lower alkyl groups,especially alkyl containing 1-3 carbon atoms and most preferably methyl.It is also preferred that the other two substituents are either aryl,e.g., phenyl, aryl lower alkyl, e.g., benzyl, fatty group or R₇. Thequaternary ammonium salts in one embodiment of the present inventioncontains two lower alkyl groups and two fatty groups. In anotherembodiment it contains two lower alkyl group and two aryl groups or twoaryl lower alkyl groups. In still another embodiment, the quaternaryammonium salt contains two lower alkyl group, one aryl or aryl loweralkyl group and one R₇.

It is most preferred that the quaternary ammonium salts contain twolower alkyl groups and two fatty groups or two lower alkyl and, one aryllower alkyl group and one R₇ group, as defined above. The preferred R₇group is

wherein R₁, Ar, R₂ and R₃ are as defined hereinabove.

In a preferred embodiment, the quaternary ammonium salt has the formula

wherein R₅ and R₆ are as defined hereinabove, R₉ and R₁₀ are lower alkyland X is a counterion.

In a preferred embodiment, the values of R₅ and R₆ are also as describedhereinabove. However it is preferred that R₅ and R₆ are bothindependently fatty groups or one of R₅ and R₆ is an aryl or aryl loweralkyl and the other is R₇.

It is preferred that R₉ and R₁₀ are independently an alkyl groupcontaining 1-3 carbon atoms. It is even more preferred that R₉ and R₁₀are the same. It is most preferred that R₉ and R₁₀ are the same andcontain 1-3 carbon atoms. It is especially preferred that R₉ and R₁₀ areboth methyl.

The quaternary ammonium salts consists of a cation portion and acounterion (anion), identified as X. The discussions hereinabovedescribed the cation portion. The counterion is a spectator ion and canbe any counterion normally used in the pharmaceutical or cosmetic arts.The preferred counterions (anions) of the quaternary ammonium salts arethe halides, especially chlorides. Especially preferred salts within thescope of the quaternary ammonium salts of the present invention includedimethyl distearyl ammonium chloride and dimethyl ditallow ammoniumchloride, and dimethyl benzyl benzethonium chloride. Of these, dimethyldistearyl ammonium chloride and dimethyl benzyl benzethonium chlorideare most preferred.

It is preferred that the amides of the present invention have theformula

or pharmaceutically acceptable salts thereof wherein R₅ and R₆ areindependently aryl, aryl lower alkyl, fatty group, or R₇ and R₄ is afatty group, as defined herein,

The preferred R₄ is an aliphatic containing 15-21 carbon atoms. Thepreferred R₄ group is completely saturated or contains 1-8 carbon-carbondouble bonds and more preferably 1-6 carbon-carbon double bonds. In oneembodiment, the R₄ group is saturated or contains 1, 2, 3 or 4carbon-carbon double bonds. The preferred R₄ is as described hereinabovefor fatty groups.

The preferred R₆ and R₅ groups are as described hereinabove.

Examples of preferred tertiary amides of the present invention includebenzethonium stearamide, benzethonium linoleamide, distearyl linoleamideand distearyl stearamide.

A first transdermal composition of the present invention includes aquaternary ammonium salt, as defined hereinabove wherein on the cationicportion, two of the substituents on the nitrogen atom are independentlyan alkyl group having 1-6, and more preferably 1-4 carbon atoms (i.e., adialkyl group) wherein each alkyl group is the same or different, andthe other two groups around the nitrogen atom are independently aryl,aryl lower alkyl, R₇, or a C₁₂-C₃₀ fatty group. The preferred quaternarysalt is as defined hereinabove. The quaternary ammonium salt isparticularly suited to the treatment of mammals, e.g., humans, sufferingfrom insect bites. Insect bites cause itching, inflammation andirritation of the skin. Without being bound, it is believed that theseconditions are usually caused by injection of formic or similar acidsinto the skin by the insect. Thus, the ammonium quaternary saltsdescribed hereinabove, which are bases having pH's above 7, act toneutralize the acidic affected skin. Moreover, the quaternary ammoniumsalts in concert with other active agents, such as antioxidants,eliminate the pain and itching associated with insect bites.

The quaternary ammonium salts of the present invention are particularlysuited for use in a transdermal composition employed in treating insectbites. Without being bound, it is believed that the long chain radical,non-polar portion of the compound forms a film that surrounds theaffected area protecting it from environmental contaminants. At the sametime, it is believed that the polar portion of the quaternary ammoniumsalt aids in neutralizing the acid-induced skin effects of the insectbite. For example, the ammonium salt, such as dimethyl distearylammonium chloride acts as a mild base which can neutralize the formicacid in insect bites. Thus, an aspect of the present invention is theuse of quaternary ammonium salts as defined herein for the treatment ofinsect bites in humans. The quaternary ammonium salts are appliedtopically in effective amounts in a treatment regimen defined by thephysician. Preferably, it is applied topically on the skin of themammal, especially humans, on the locus of the area of the bite in anamount sufficient to be completely rubbed onto the skin, said amountvaries depending on several factors, e.g., nature and extent of theaffected area, the age of the patient, and the like. Preferably, theamount applied ranges from about 0.3 g to about 1.0 g and morepreferably from about 0.5 g to about 0.75 g per 75 kg mammal. Thequaternary ammonium salts may be carrier free or may be combined with apharmaceutical carrier normally used in the pharmaceutical arts to forma pharmaceutical composition, the latter being more preferred.

A second aspect of the present invention is the reaction product (“firstproduct”) of the quaternary ammonium salt and a fatty acid as describedhereinabove containing 12-30 carbon atoms, or a salt thereof, as definedherein. The preferred fatty acid contains 16-22 carbon atoms. Thepreferred fatty acid is stearic acid. The reaction is effected undereffective conditions. It is preferred that the reaction is conducted inaqueous medium, especially water. It is also preferred that the reactionis conducted with equivalent amounts of the ammonium salt and the fattyacid, although ratios ranging from about 1:10 to about 10:1 may be used.The reaction is effected at temperatures above the melting point of thefatty acid. At the conclusion of the reaction, the pH of the solutiondecreases very quickly, after formation of the product. For example,when Varisoft, which is dimethyl distearyl ammonium chloride, is reactedwith stearic acid at a temperature greater than the melting point ofstearic acid, i.e., at a temperature greater than about 50° C., the pHdrops exponentially from 5-6 down to 2-3 within minutes of forming theproduct, dimethyl distearyl ammonium stearate.

The initial reaction product resulting front the reaction of thequaternary ammonium salt and the fatty acid is a quaternary ammoniumsalt fatty acid complex, hereinafter also referred to as an ion pair.

This reaction product is also useful and can be combined with thequaternary ammonium salt, described hereinabove to form a secondtransdermal composition.

The second transdermal composition of the present invention is anantiseptic scrub composition employed to remove microorganisms presenton objects, such as walls, floors, cabinets, windows, toys, utensils,machinery, doors, toilets, sinks, and the like and to killmicroorganisms that are not removed.

The problems associated with antiseptic compositions of the prior artare that they include aggressive detergents and microphobes which are soirritating to the skin that they can make affected portions of the roughskin chapped and/or irritated. The second transdermal compositionaddresses these problems.

The molar ratio of the quaternary ammonium salt and the reaction productof an ammonium salt and a fatty acid (first product) are such that themolar ratio of ammonium salt to the first product is in the range ofbetween about 10:1 and about 1:10. More preferably, this molar ratio isin the range of between about 5:1 and about 1:5. Still more preferably,this molar ratio is in the range of about 1:2 to about 2:1. Mostpreferably, the molar ratio is in the range of about 1:1. The secondtransdermal composition may also contain the antiseptic detergents ofthe prior art. If present, the antiseptic detergent is present ineffective amounts to kill the unwanted microorganisms.

In addition, this second transdermal composition may be carrier free orassociated with a carrier normally used in the pharmaceutical orcosmetic arts.

Although the invention is independent of any theory explaining itseffectiveness, it is believed, without wishing to be bound, that theammonium salt provides a protective film to the skin surface while thefirst reaction product heals the skin of the deleterious effect of theantiseptic active agents. In any event the second transdermalcomposition, used as an antiseptic agent, for example, as a scrub wash,provides soft, smooth microbiologically benign skin.

A third aspect of the present invention is directed to the reactionproduct of a quaternary ammonium salt and a fatty acid, or salt thereof,i.e., the (“first product”) as defined in the second embodiment, in anaqueous medium, such as water, at a pH less than 4.5 optionally in thepresence of a catalytic effective amount of a nitrogenous organic base,for sufficient time for a stable product (“second product”) to form.This reaction forms the tertiary amide described hereinabove. The molarratio of the quaternary ammonium salt and the fatty acid is the same asused in the preparation of the first product. The reaction is effectedunder conditions sufficient for a product different from the firstproduct to be formed. i.e., for the tertiary amide to be formed. It ispreferred that if a base is utilized the base used is an alkanolamine,or alkylamine especially a lower alkanolamine, or lower alkylamine,i.e., an alkanolamine or alkylamine, containing 1-6 carbon atoms in thealkanol or alkyl portion thereof, respectively, and more preferably 2-4carbon atoms in the alkanol or alkyl portion thereof, respectively. Theamine may be substituted with 1, 2 or 3 alkyl groups or alkanol groupsor combination thereof. It is especially preferred that the organic baseis a triloweralkanolamine, such as e.g., triethanolamine. Examples ofthe nitrogen containing base include triethanolamine, trimethanolamine,trimethethylamine, triethylamine, tromethamine or a trisaminoalcohol,such as tris(hydroxymethyl)aminomethane or tris(hydroxyethylmethyl)aminoethane. Of these, triethanolamine and tromethamine are thepreferred species; the most preferred organic base is triethanolamine.The reaction is effected at a temperature sufficient for a tertiaryamide product to form, preferably above the melting point of the fattyacid. Preferably the reaction is effected, above about 60° C. at 1 atmpressure up to the boiling point of the aqueous solvent, i.e., about 100C. When the quaternary ammonium salt undergoing the reaction contains amethyl group substituent, it is noted that under the reactionconditions, bubbling in the water is observed, indicating that a gas isevolved. For example, if the quaternary ammonium salt has a methylsubstitutent thereon, under the reaction conditions, bubbles areobserved indicating that a gas is evolved. Without wishing to be bound,it is believed that the gas is methanol. Moreover, if the quaternaryammonium salt undergoing the reaction is originally a salt of dimethyldistearyl ammonium chloride, a product of the reaction is distearylstearamide, a tertiary amide.

The reaction is effected optionally in the presence of effective amountsof the nitrogenous (nitrogen-containing) organic base to catalyze theformation of the tertiary amide. Preferably, the organic base, ifpresent, is present in a total molar amount ranging from about 0.02 toabout 1.0 and more preferably from about 0.30 to about 0.6 and mostpreferably from about 0.16 to about 0.50 mole thereof per each mole ofquaternary ammonium salt. Preferably, the nitrogenous organic base, ifutilized, is added into two separate additions, with the molar amount ofnitrogenous organic base present in each addition ranging from about0.01 to about 0.5, more preferably from about 0.15 to about 0.3 and mostpreferably from about 0.8 to about 0.2 mole per each mole of quaternaryammonium salt.

If however, the quaternary ammonium salt contains an aryl moiety whichmay be bonded to the nitrogen atom in the ammonium salt directly orindirectly through an alkylene bridge, e.g., benzyl group or if R₇ ispresent on the nitrogen atom, then a catalyst is optional.

The tertiary amide is formed by reacting the quaternary ammonium saltwith a fatty acid R₈ COOH in an aqueous solvent under conditionseffective as described herein to form the amide. The ammonium salt andthe fatty acid are present in effective amounts to form the tertiaryamide. Preferably, the molar ratio of ammonium salt to fatty acid rangesfrom about 10:1 to about 1:10 and more preferably from about 5:1 toabout 1:5 and even more preferably from about 2:1 to about 1:1. However,it is most preferable that the molar ratio is about 1:1.

As the neutralized mixture cools, a second acid hydrate forms. This acidhydrate is stable at neutral pH. When the hydrate is forming, it formsan emulsion. Formation of the hydrate is slow and is not complete untilthe emulsion is at ambient temperature. The rises as hydronium ion isremoved from solution. Without wishing to be bound, it is believed thatthe hydrate forms with three tertiary amides.

FIG. 4 illustrates this rise in pH as the amide hydrate forms. In FIG.4, Varsoft and benzethonium chloride were reacted with stearic acid toform the tertiary amide. The tertiary amide formed an emulsion. Theemulsion is neutralized and made into a finished product. The pH of theproduct was measured as it cooled to ambient after Carbomer, apolyacrylate thickening agent was added. Carbomer lowers the pH forabout 15 minutes as it hydrates (data not shown). The data in FIG. 4begin after Carbomer hydration is complete and continues until after theproduct reaches ambient temperature. The pH rises as the emulsion cools.The pH rise is a direct response to the removal of protons from solutionas the tertiary amide hydrate is formed. Without wishing to be bound, itis believed that the hydrate has the formula(tertiary amide)₃.H₃O+.

Without wishing to be bound it is believed that the quaternary salt andthe fatty acid initially produce a quaternary ammonium fatty acid ionpair, in which the ammonium salt and the fatty acid moieties are notcovalently bonded, but are held together by electrostatic forces, suchas ion dipole interactions, and the like. This ion pair is the firstproduct described hereinabove. It is noted that when the fatty acid andthe quaternary ammonium salt react, the pH falls rapidly. Thus hydrogenions are generated, from the ion pair formulation. The ion pairs canhydrogen bond with the hydrogen ions to form an acid hydrate (protonatedion pair) and remove a proton from solution.

When the protonated ion pair is formed, the pH rises again and thehydronium ion is removed from solution.

If R₅ and R₆ are a fatty group and the nitrogenous base, as definedhereinabove, is not present, the reaction may just form the ion pair orprotonated ion pair, which may be isolated. However, if R₅ and R₆ arearyl containing groups, such as aryl, arylalkyl and/or R₇, then the ionpair may be a fleeting intermediate and the product may proceed to formthe tertiary amide.

Without wishing to be bound, it is believed that the protonated ion pairnext undergoes a dealkylation reaction, in which R₉ and R₁₀ react withwater to form an alkanol.

For example, in the quaternary ammonium salt, if R₉ and R₁₀ are methyl,methanol is given off. As indicated hereinabove, a sufficient amount ofthe catalyst, e.g., weak nitrogenous base, as defined above may bepresent in amounts sufficient to effect the dealkylation reaction.However, the base is present in sufficient quantities to prevent hardgel formation. It is noted, however, that in some instances, thecatalyst may not be needed. For example, when R₅ and R₆ contain an arylgroup, such as aryl alkyl or R₇, then a catalyst may not be required toeffect the dealkylation. As a result of the dealkylation reaction, atertiary amide is formed.

Without wishing to be bound, it is believed that the tertiary amide isformed when the two alkyl groups of R₉ and R₁₀, e.g., such as methyl, ofthe quaternary ammonium salt, are attacked by a water molecule. The pHfalls as the hydronium ion is released; however, as the reactiontemperature cools, a tertiary amide hydrate is formed.

Without wishing to be bound, it is believed that the dealkylation occursby one of the following reaction mechanisms. In one mechanism, the ionpair loses one methyl group by forming methanol with a proton and thecarboxylic oxygen atom of the carbon moiety of the fatty acid andbecomes an unstable quaternary amide; the methanol is released from theammonium salt. Then, the second methyl group reacts with water to formthe methanol and regenerates a proton and the stable tertiary amide,thereby causing the pH to fall. Alternatively, three ion pairs form anacid hydrate, removing a proton from the aqueous solution, therebycausing the pH to rise. One of the ion pairs reacts with water and theoxygen atom of the carboxy moiety and the fatty acid to form twomethanols. The acid hydrate falls apart and releases a proton into theaqueous solution, thereby causing the pH to fall. The remainingunreacted ion pairs form yet another acid hydrate and the pH cycles upand down.

The rate of the reaction to form the tertiary amide is dependent uponthe identity of the groups on R₄ and R₅. For example, where R₄ and R₅both contain an aromatic moiety, the amide formation is faster than whenR₄ and R₅ are only fatty groups. Moreover, the amide is formed fasterwhen the fatty acid used as catalyst has a shorter chain. For example,if R₈ COOH contains 16 carbon atoms, amide formation occurs faster thanif it contained 26 carbon atoms. Moreover, if R₈ is unsaturated, withone or two double bonds, amide formation is faster than if R₈ iscompletely saturated.

The various stages are illustrated graphically in FIG. 5. In FIG. 5,benzethonium chloride was titrated into a CLA: water mixture at 70° C.The pH response was monitored as a function of benzenthonium chlorideadded (unsaturated fatty acid initially in excess). There are fivedistinct stages clearly shown in the reaction sequences:

1. In stage 1, the pH drops rapidly as the ion pair and proton areformed.

2. In stage 2, the ion pair acid hydrate forms, removing a proton fromsolution and raising the pH.

3. In stage 3, the ion pair acid hydrate reaction and the tertiary amideformation are occurring simultaneously. One removes a proton the otherregenerates a proton. The pH oscillates back and forth at the beginningof this stage then increases slowly.

4. In stage 4, the ion pair acid hydrate converts into the tertiaryamide, releases methanol and regenerates a proton.

5. In stage 5, there is no more unreacted fatty acid and the pHstabilizes.

This is the general scheme of the reactions for forming the tertiaryamide. After stage 5, however, the pH rises as protons are removed fromsolution as the positively charged hydrate forms.

The formation of the tertiary amide is inhibited if calcium is present,such as aloe Vera. Aloe Vera contains high levels of calcium. Withoutwishing to be bound it is believed that calcium can bind with the fattyacids to interrupt the ion pairing mechanism.

Further, if the pH rises above 5, such as by the addition of EDTA oreven excess amounts of the nitrogenous containing catalyst describedabove, then the amide formation is inhibited. These reactions can raisethe pH to a level wherein the ion pair hydrate is stable, thusterminating the reaction sequence. Under such conditions, a gel mayform.

It is to be also noted that if the quaternary ammonium compound ispresent in high concentrations, greater than a 10:1 molar ratio relativeto the fatty acid, a thick gel is formed. In either case, the gel tendsto inhibit the formation of the amide. Without wishing to be bound, itis believed that the gel inhibits the molecular movement needed toorient the ion pair in the acid hydrate. The resulting mixture, the gel,is metasable. If more water is added, the gel dissipates and the amideis generated in situ.

Further, for the reaction to be effected, the temperature of thereaction between the quaternary ammonium salt and the fatty acid isconducted preferably at least above the freezing point of the fatty acidand below the 100° C. boiling point of water, whichever temperature islower.

It has been found that tertiary amides are effective in penetrating thelayers of the skin. Further, the aromatic containing tertiary amidesi.e., tertiary amides in which at least one of the substituents on theamide contains an aryl containing group, e.g., aryl, aryl alkyl or R₇are more effective in penetrating the skin than the non-aryl containingtertiary amides i.e., tertiary amides in which all of the groups on theamide are fatty groups. If the fatty group on the tertiary amides,especially the aryl containing tertiary amides is unsaturated, then thetertiary amide penetrates more deeply into the skin as a carrier.

For example, benzethonium stearamide (BSA) penetrates shallowly into theskin and forms a protective fat loving layer on the skin. If it is usedin combination with beeswax and povidone, the combination provides askin protectant that can protect the scalp for thirty minutes fromtreatment with a highly alkaline hair relaxer.

On the other hand, if the fatty group contains carbon-carbon doublebonds, and in addition if the tertiary amide contains aromatic moietiesthereon, especially two aromatic moieties, the amide penetrates moredeeply into the skin. For example, benzethonium linoleamide (BLA)penetrates deeply into the skin, thereby bringing an activeantimicrobial agent into intimate contact with the skin surface. Incombination with a nutrient, it enhances the healing rate of hums andcuts. BLA has a strong characteristic smell of unsaturated fatty acid.When rubbed into the skin, there is substantially no characteristic odoron the skin surface and there is a readily perceived greasy coating onthe skin. It is believed that the unsaturated fat is within the stratumcorneum (SC) and the aromatic substituents on the amide are above andoutside the SC.

Moreover, tertiary amides such as BLA, in which the nitrogen amide issubstituted with two aryl containing groups and a third group,

wherein R₈ is unsaturated are important in sustained pain-free growth ofnew skin granules.

Without wishing to be bound, it believed that chronic wounds aretypically nutrient poor and circulatory poor sites. Excessivestimulation causes pain as blood rushes back into little usedcapillaries. BLA and other tertiary amides of this class is described inthe following paragraph, allows the metering of growth-stimulatingnutrients into the chronic wound site.

This effect is more prevalent if a mixture of tertiary amides is appliedto the skin, especially two tertiary amides in combination, where theyeach contain a tatty acid moiety containing 1-8 carbon-carbon bonds asdefined herein and more preferably 1-6 carbon-carbon double bonds. It ispreferred that at least one of the amide has an aromatic group, i.e.,aryl or aryl alkyl or R₇ substituted thereon. It is preferred that thetwo tertiary amides are present in a molar ratio ranging from about 10:1to about 1:10 and more preferably from about 7.5 to 1 to about 1 toabout 7.5 and most preferably from about 3:1 to about 1:3. It ispreferred that if one of the tertiary amides have an aromaticsubstituent thereon, that it is present in the smaller about relative tothe tertiary amide having no aromatic moiety thereon, for example, justhaving fatty groups thereon. Under these circumstances, an enhancedstimulation is effected. For example, if distearyl linoleamide (DSL) isadded to BLA in a molar ratio ranging from about 10 to about 1 and morepreferably from about 7.5 to about 1 and most preferably from about 3 toabout 1, stimulation is more enhanced. However, pain may be felt fromthis enhanced stimulation. But the pain resulting therefrom can becontrolled by adding a topical analgesic such as lidocaine.Nevertheless, healing is fastest when two tertiary amides are usedtogether in effective amounts. In addition, an occlusive moisturebarrier, such as beeswax, can be used in chronic wound care productswhen tertiary amides are used, especially if more than one tertiaryamide is utilized, such as BLA and DSL to keep the wound moist. If morethan one tertiary amide is utilized, then the tertiary amide is presentin effective amounts as above. The beeswax is present in amountsufficient to keep the wound moist, preferably from 0.5 to about 1.5% byweight of the composition. However, where the intact skin is quitethick, such as the skin on the foot, the mixture of aromatic andaliphatic unsaturated tertiary amides, that is, amides in which on oneamide, one of R₄, R₅ and R₆ are fatty groups, wherein at least one ofthe fatty groups is unsaturated and in the other one of R₄, R₅ and R₆ isa fatty group which contains unsaturation and the other two groupscontain an aromatic functionality such as R₇, aryl lower alkyl, and thelike, is quite useful as a carrier. Together, in combination they canpenetrate the thick skin as more penetration is required to open thepores sufficient enough to allow nutrients into a thick skin site.

Aliphatic saturated tertiary amides, that is, tertiary amides in whichR₄, R₅ and R₆ in the above Formula are only saturated fatty groups,slightly penetrate the skin, allowing moisture to flow out of andfunctional ingredients, such as nutrients to flow into the stratumcorneum (SC). In the absence of an occlusive moisture barrier (eg.,beeswax), an aliphatic saturated tertiary amide, e.g., DSS dries out theskin. This property is useful in closing a wound where drying out isimportant in forming a full durable wound closure. However, with anocclusive barrier, the aliphatic saturated tertiary amides are aneffective moisturizer.

The amide hydrates discussed hereinabove are also an effectivetransdermal carrier; when it is present in effective amounts, they openup the pores and increase the permeability of the skin.

It is to be noted that the amide hydrate forms an emulsion as it coolsand may even form a gel, a cracked crust which is unappealing to view.However, applying a shear thereto at a sufficiently high shear rate tocause non-Newtonion flow, air can be whipped therein. As a result, thegel is broken, reformed and the embodiment transformed into a smoothuniform cream.

The tertiary amide or hydrate can also act as a skin protectant whenpresent in skin protecting effective amounts. By skin protectant, it ismean protecting the skin of the mammal from chapping, cracking orcontact dermatitis. The preferable amounts are in the ranges indicatedhereinabove.

When the tertiary amide hydrate is rubbed onto the skin, it driescompletely in about 10 seconds. The dry surface is non sticky and feelslike a rubber glove is bonded to the skin. However, it protects the skinfrom non-ionic surfactants.

Nonionic surfactants, such as Triton X-100 and Nonoxynol-9 and the likeare present in many emulsions. These degreasing surfactants areirritating and sticky on the skin.

However, the nonionic detergents can be layered on top of the amide sothat they are physically not in contact with skin. As a result, normallyirritating ingredients can be added that are not irritating in use. Theyare present in degreasing effective amounts. More specifically, they arepresent in amounts ranging from about 1 to about 10% and more preferablyfrom about 2 to about 8% and most preferably from about 4 to about 6% byweight of the composition.

Nutrients and other non-film-forming compounds can be added as anotherlayer on top of the detergent in effective amounts. These nutrients areabsorbed into the skin at a rate governed by the concentration of theamide on the skin surface. These nutrients include methyl sulfonylmethane (hereinafter “MSM”), pyrrolidone carboxylic acid (hereinafter“PCA”), Vitamins A, D and K. In addition, they are present in amountsranging from about 0.5% to about 3% and more preferably from about 1% toabout 2% and most preferably from about 1% to about 1.5% of thecomposition.

A wax layer may be deposited on the nutrient layer, making a uniform,high friction film on the skin surface. The wax film is occlusive andprevents moisture from leaving the skin. The wax layer is present inmoisture retarding effective amounts. Preferably, it is present inamounts ranging from about 0.1% to about 2% and more preferably fromabout 0.5% to about 1.5% and most preferably from about 0.8% to about1.2% of the transdermal composition. The wax film has an unpleasant handfeel because the coefficient of friction is so high.

Finally, a water-soluble polymer, povidone e.g., polyvinyl pyrolidone(PVP) is added. The polymer is the last layer to deposit and imparts asilky soft hand feel. It is present in amounts ranging from 0.3% toabout 3% and more preferably from 0.5% to about 1.5% by weight of thecomposition.

Without wishing to be bound, it is believed that detergents control thelayering of compounds. The tertiary amide acid hydrate has a netpositive charge. Intentionally-unreacted cationic surfactants tend toemulsify uncharged waxes, not positively-charged acid hydrates.

The cationic-surfactant-emulsified wax competes with nonionic-emulsifiedacid hydrate for the negative charge on the skin surface. But the acidhydrate penetrates the SC, giving it a long term advantage over thepositively-charged wax. Once the positively-charged acid hydrate ispermanently bonded to the SC, the positive charge repels thecationic-wax, creating the first layer.

The nutrient package is nonionic and precipitates after the first layeris formed. As drying continues the intermediate nonionic layer buildsup. With increasing distance from the first layer's positive charge, thecationic-wax precipitates and forms a continuous film over theintermediate layer.

The most water soluble film former is povidone. It is the last to dry,so it forms a final film over the first three layers. Povidone has asilky smooth hand feel.

Different products can be made by mixing and matching the layers

For example, a product without the wax and polymer layer allows moistureloss from the skin. This feature is used to let skin surfaces dry outand become durable, tough outer skin.

When rapid absorption of nutrients is desirable, a high concentration ofvarious tertiary amides such as benzethonium linoleamide (BLA),disteraryl linoleamide (DSL), benzethonium stearamide (BSA) and cetylglycerol laurate (CGL), are used to open the pores for rapid absorption.Preferably these tertiary amides are present in a total amount rangingfrom about 5% to about 12% and more preferably from about 7% to about10% and most preferably from about 8% to about 9%. It is preferred thatthe molar ratio of CGL/DSS/DSL/BLA is about 100/30/20/3. Conversely,when a lower absorption rate of nutrients is desired, for example over24 hours, only BLA and DSL are used. Preferably they are present inamounts ranging from about 3% to about 4% of the composition. When noabsorption is desired, the amide is not present.

The tertiary amides may be prepared by premixing. Premixes are used tosimplify processing by executing some of the chemistry separately in amore concentrated formula. By premix, it is meant the composition of theformulation is a mixture of stages 2-5, as described hereinabove inreference to FIG. 5. The premix contains predominantly the tertiaryamide in greater than about 50% by weight of the tertiary amide (stage4) and more preferably greater than 75% by weight of the tertiary amide.It is in gel form that inhibits formation of the amide hydrate (stage5). However, when placed in water, the premix can spontaneously movethrough all 5 stages to form the amide hydrate.

The concentration of the premix materially changes the physicalchemistry. The aromatic tertiary amide reaction is driven to completionby adding all the fatty acid with the benzethonium chloride (stearicacid:benzethonium chloride mole ratio=2). The aliphatic tertiary amidereaction is incomplete (Varisoft:remaining stearic mole ratio=1) becausethe viscosity of the mix prevents most of the ion pair acid hydrate fromdemethylating to the tertiary amide. The combination results in a phasestable grease, rather than a water/solid two phase mixture. The singlephase grease is easier to handle than a two phase fluid.

When a premix is added to the main mix and diluted with water such thatthe tertiary amide can form, the previously incomplete reaction now goesto completion.

Premixes of unsaturated fats are somewhat different than premixes ofsaturated fats because the unsaturated fats are liquid at roomtemperature and are harder to make phase stable.

As previously described, the quat/fatty acid conversion to a tertiaryamide goes through a meta stable acid hydrate step. Thus, there arebelieved to be two acid hydrates that can form, one with the ion pair,an intermediate which is meta stable and one with the tertiary amidewhich is stable and a final product. This step forms a gel at higherconcentrations, such as in a premix. If the gel is too thick, then theion pair acid hydrate formation/demethylation step cannot take place. Itis believed that this step forms/deforms and forms again over and over,possibly because only one leg of the ion pair acid hydrate converts tothe amide at a time. When this amide is formed, the ion pair acidhydrate breaks up. The two remaining ion pairs find a third ion pair andreform the ion pair acid hydrate. This iterative process goes back andforth until all ion pairs have converted to the tertiary amide. Oncecooling begins, the tertiary amide can begin to form the phase stablefinal acid hydrate.

The ion pair acid hydrate is a visible gel; the amide formation releasesvisible gas and breaks the gel. The pH rises as the gel forms (pH risesas a proton is removed from solution), then falls as the tertiary amideis formed (pH falls as the proton tied up in the acid hydrate isreleased back into solution).

If the gel is too strong, this iterative process is interrupted andconversion to the tertiary amide is low. There are many factors thatinfluence the strength of the gel:

Absolute Concentration—

If the concentration of the reactants is too high, there is not enoughfree water to circulate the mix without shear, it would be expected toincrease the rate of reaction by increasing the concentration ofreagents. This is true only up until that point where gel formationprevents the iterative physical process of forming/deforming/reformingthe ion pair acid hydrate. [The absolute concentration is determinedexperimentally, because the ratio of unsaturated to saturated fattyacids and the different quats all affect the onset of excess gelation.]

Shear Thickening—

Most fluids are Newtonian or are shear-thinning. Cationic surfactantsystems are known to be shear thickening, that is, the more the fluid issheared, the thicker the fluid becomes. This is true of the premixesdescribed herein. If there is any shear in the system, a gel forms thatinhibits the conversion to the tertiary amide. For example, the mix canbe stirred slowly without gel formation. With only mild wiping, forexample with a spatula, visible gel forms. When the spatula is removed,the gel breaks and a smooth fluid reemerges.

Gas Release—

The aromatic tertiary amides are particularly sudsy. Suds tend to creategels that inhibit the conversion to the tertiary amide. For example, theunsaturated aromatic amides are more sudsy than the saturated aromaticamides. If the unsaturated fatty acid, aromatic and aliphatic quats aremixed together, the gas formed by the faster-reacting aromatic quatinhibits the conversion of the aliphatic quat to the tertiary amidebecause the released-gas dissipates slowly and a gel is formed. Thesolution is to complete the reaction of the aromatic quat first, allowtime for the gas to dissipate, then begin the reaction of the aliphaticquat.

Process Thinning—

Organic bases, especially triethanolamine (TEA) are used as a processaid to prevent permanent gel formation. Low levels of TEA tend to thinthe mixture and break the gel. However, TEA also increases the pH. AtpH>5, the aromatic quat/fatty acid converts to the tertiary amidereadily, but the aliphatic quat does not. The aliphatic reaction rategoes rapidly at pH<4. If the TEA/quat mole ratio is about 0.1, then thegel thinning occurs and the reaction pH is <4.

Premix Manufacturing—

The best way to make premix is to react the aromatic quat with excessfatty acid, with the TEA/aromatic quat mole ratio=0.1. Sufficient timeis allowed for the gas to be generated and released. The reactiontemperature is preferably 80-90° C. and the mix is stirred just enoughto insure circulation. When the gas is substantially released, aliphaticquats are added equal to the moles of unreacted fatty acid remaining.Additional TEA is added such that the total TEA added equals 0.1 timesthe aliphatic quat concentration. The secondary gas release from thealiphatic tertiary amide formation is much slower than the aromatic gasrelease. A gel forms right after the aliphatic quat is added; the gelbreaks and the mix flows at low stirring rates; a slow release of gasoccurs until the reaction is substantially complete. When the gasrelease is substantially complete, the mix can be cooled to aphase-stable grease. The total solids concentration is determinedexperimentally based on the relative ratios of aromatic/aliphatic andunsaturated/saturated fatty acids. Typical initial solids concentrationsrange from 30-50%.

The second product and the amide hydrate thereof of the presentinvention is useful separately or in conjunction in a mixture as avehicle for transporting molecules to the skin. When used as a carrier,the second product and/or its amide hydrate are present in carriereffective amounts. This second product (amide) and/or its hydrate helpcarry active agents, such as pharmaceuticals, cosmetics, and the like tothe skin or epidermis. Thus, this second product and the hydrate arepresent in the transdermal composition in amounts effective for theactive compound to be transported to the skin. Preferably the secondproduct and/or the hydrate separately or in combination are present as acarrier in at least 0.2% (w/w) of the transdermal compositions and morepreferably from about 0.3 to about 10%(w/w) of the transdermalcomposition and more preferably from about 0.4 to about 7% (w/w) andmost preferably from about 2 to about 6%(w/w) of the transdermalcomposition. It is preferably present in a weight ratio ranging fromabout 0.1 to about 30 relative to the active agent and more preferablyfrom about 1 to about 24 relative to the active agent and mostpreferably form about 10 to about 20 relative to the active agent.

It has been found that the ability of the carrier defined hereinabove topenetrate the skin is dependent upon the amounts of the carrier presentrelative to the active agent. At the higher weight ratios of carrier toactive ingredient, such as above about 20, there will be a largetransdermal effect, such that the transdermal composition containingcarrier will penetrate the skin, on the other hand, at the lower ratioof carrier to active ingredient such as about less than 5, there will bea small transdermal effect, and the transdermal composition containingthe carrier will only partially penetrate the skin. At the interimratio, the transdermal composition containing carrier will penetrate theskin partially, to a greater extent than at the lower ratios but not asmuch as at the higher ratios.

Thus, by controlling the ratios, one can control the amount ofpenetration of the transdermal compositions comprising carrier andactive ingredient associated therewith into the skin.

A fourth aspect of the present invention is the reaction product of afatty alcohol containing 12-30 carbon atoms which may be saturated orunsaturated with a fatty acid as defined hereinabove under ester formingeffective conditions, which ester is reacted with a monoglyceride toform an ether, the final product being an ether-ester (third product).It is preferred that the fatty alcohol contains 16-22 carbon atoms andis either completely saturated or contains 1-8 carbon-carbon doublebonds and more preferably 1-6 carbon-carbon double bonds and mostpreferably 1-3 carbon-carbon double bonds. More preferably, the fattyalcohol contains between about 12 to about 18 carbon atoms. Still morepreferably, the fatty alcohol is cetyl alcohol or myristic alcohol. Mostpreferably, the fatty alcohol is cetyl alcohol.

The fatty acid ester reacts with a monoglyceride. The monoglyceride isformed from the reaction of glycerol with a fatty acid containing 10-26carbon atoms under esterification conditions. Preferably the reaction iseffected in the presence of an acid. The preferred alcohols contain from16-22 carbon atoms. Although the ester may be formed at the 1 or2-position of the glycerol, it is preferred that the ester is formed atthe 1-position of the glycerol. The fatty acid esterified to themonoglyceride may be saturated containing no-carbon-carbon double bondor unsaturated containing up to eight carbon-carbon double bonds. Themonoglyceride may additionally be substituted. For example, thesubstituents may be one or more alkyl groups, preferably one or moreC₁-C₆ alkyl. The monoglyceride is additionally preferably saturated. Aparticularly preferred monoglyceride is glycerol monolaurate.

It is important to appreciate that this third reaction product from thereaction of monoglyceride with the fatty acid ester is conducted in anacid environment. That is, the third reaction product is formed in areaction mixture where the pH is less than about 4.5. The product of thereaction is an ether-ester. The monoglyceride reacts with the fatty acidester in an effective amount to form the ether-ester product.Preferably, the fatty acid ester and the monoglyceride are present inabout equimolar amounts although the molar ratio may range from about1:10 to about 10:1. For example, when cetyl alcohol is reacted withstearic acid at a pH less than 4.5, the product formed is cetylstearate. Moreover, when cetyl stearate is reacted with monoglycerollaurate at pH<4.5, the product is cetyl glycerol laurate (anether-ester).

The third product is also useful as a vehicle or carrier transportingthe active component to or through the epidermis of the mammal, e.g.,human. It is present in the transdermal composition in carrier effectiveamounts to transport the active agent to the area of treatment on theskin or through the skin. Preferably the carrier is present in at least1% (w/w) of the transdermal composition and more preferably from about 2to about 10% (w/w) of the transdermal composition and even morepreferably from about 3 to about 8% (w/w) of the transdermalcomposition. It is present in a weight ratio of about 1 to about 120relative to the active agent and more preferably from about 2 to about110 relative to the active agent and more preferably from about 20 toabout 40 relative to the active agent. This product, however, can eithercarry the product to the skin or through the dermis. Again, as with theother carrier described herein, the greater the weight ratio of thethird product to the active ingredient, the greater is the ability ofthe transdermal composition containing the same to penetrate the dermis.Thus, in a larger ratio, e.g., greater than about 20, this product willpenetrate the epidermis to a larger degree than if the ratio is lessthan about 5, wherein there will be a slight penetration of the dermis.If the ratio is intermediate therebetween, the transdermal compositionwill penetrate the dermis to a greater degree than that a compositionhaving lower ratio but less than at that of a composition having ahigher ratio.

It is believed that the third product has the formula

wherein R₁₀₀, is a fatty group, having 11-29 carbon atoms and R₁₀₁ andR₁₀₂ are independently a fatty group containing 12-30 carbon atoms.

It is more preferred that R₁₀₁ and R₁₀₂ contain an even number of carbonatoms. It is even more preferred that R₁₀₁ and R₁₀₂ independentlycontain 16-22 carbon atoms. Further, it is preferred that R₁₀₀ containsan odd number of carbon atoms. It is even more preferred that 16-22carbon atoms and R₁₀₀ contain 15-21 carbon atoms. R₁₀₀, R₁₀₁ and R₁₀₂may contain 0-8 carbon-carbon double bonds and more preferably 0-6carbon-carbon double bonds. In one embodiment, it may contain 0carbon-carbon double bonds or 1-3 carbon-carbon double bonds.

A third transdermal composition of the present invention compriseseither the amide (the second product defined hereinabove) or the amidehydrate or the third product or both the amide and the third product inassociation with the quaternary ammonium salt as described hereinabove.The amide (second product) or amide hydrate or the third product or thecombination of the third product with the amide (second product) oramide hydrate is present in carrier effective amounts, while thequaternary ammonium salt is present in pharmaceutically effectiveamounts. Thus, as described herein a pharmaceutical compositioncomprising the quaternary ammonium salt in effective amounts, asdescribed hereinabove and the second product or the hydrate, or thethird product (ether ester), either each alone, or in combination, asthe pharmaceutical carrier would be useful for treating bug bites inhumans. Moreover, if antioxidants as defined hereinabove are alsopresent, in anti-oxidizing effective amounts, the composition is alsouseful for alleviating pain and itching associated with insect bites.

Moreover, when the first product described hereinabove, i.e., thereaction product of the nitrogenous ammonium salt with a fatty acid isadded to the third product in combination with the detergent asdescribed hereinabove, the composition is useful as an antiseptic scrubcomposition.

The present invention is directed to other embodiments.

A fourth transdermal composition is useful in healing subcutaneousbruising. The composition contains either the first, second, or thirdproduct in carrier effective amounts of the present invention incombination with active agents in therapeutically effective amounts.Such bruising is common in humans of advanced age who are often bruisedover much of their bodies, especially their outer extremities. Suchbruising is treated by applying this fourth transdermal compositionscontaining nutrients, such as olive oil, herbs and antioxidants inanti-oxidizing effective amounts. These nutrients are present in amountseffective in eliminating subcutaneous bruising.

Thus, the fourth transdermal composition is a combination of any one ofthe carriers described hereinabove transporting nutrients through theskin to the site of the bruise. The second product or amide hydrate orthird product are present in carrier effective amounts as describedhereinabove. Additionally, the application of the fourth transdermalcomposition to the skin increases blood circulation. This latterproperty is immediately apparent due to the increased pink color intreated areas of the skin as soon as about 1 to 2 minutes after rub-inof the composition. However, if the desire is to transport the activeagent through the dermis, the preferred carrier of the present inventionis the third reaction product (ether-ester) which is present in carriereffective amounts as described hereinabove. If the desire is totransport the active agent to the epidermis, the preferred carrier isthe second reaction product (amide) or hydrate alone or in combinationin effective carrier amounts, as defined herein.

A fifth transdermal composition is useful for treating skin irritations,diaper rash. The skin problems generically referred to as diaper rashextend to humans at the early and late portions of life. That is,infants, as well as the elderly, are subject to the skin problem definedas diaper rash.

Although diapers absorb much of the moisture and bodily discharge, stillskin in areas protected by diapers are chronically wet resulting in theformation of rashes and, serious skin infections. This problem isaddressed by the fifth transdermal composition.

This transdermal composition includes the quaternary ammonium salt andthe second reaction product or amide hydrate alone or in combination. Asin the previously described compositions in which the quaternaryammonium salt is a component, the function of the quaternary ammoniumsalt in this composition is to form a protective film about the skinwhile the second or fourth reaction product provides the means by whichthe active agent or agents, the healing compounds, are transdermallyconveyed from the skin surface to the damaged layers of the skin. Thus,the two components provide healing and protection. The carrier molecule,second reaction product or hydrate or the third reaction product aloneor in combination is present in carrier effective amounts, as definedhereinabove. Moreover, the quaternary ammonium salts are present inpharmaceutically effective amounts, which are the same as definedhereinabove, to form a protective film about the skin. In a preferredfifth transdermal composition, beeswax is additionally present. Aparticularly effective diaper rash composition includes the fifthtransdermal composition and a film forming compound. The film formingcompound, preferably beeswax, or beeswax and povidone (polyvinylpyrolidone), a high molecular weight film forming polymer, is combinedwith the quaternary ammonium salt in effective amounts to form aprotective film on the skin.

The preferred concentration of the amide and the quaternary ammoniumsalt in this transdermal composition is such that the molar ratio of thetotal of the second reaction product or hydrate or third reactionproduct present to the quaternary ammonium salt is in the range ofbetween about 0 to about 5, more preferably from about 0.5 to about 4and most preferably from about 1 to about 2.

A sixth transdermal composition within the scope of the presentinvention is employed primarily as a treatment of other skin chafings,e.g., bed sores. Bed sores are the direct result of lingering pressureon the skin of a bed ridden, immobile human beings. This pressuremanifests itself in the development of sores which grow progressivelymore serious as manifested by increasing red color culminating in theirmore serious manifestation of the breaking open of the skin. Transdermalcompositions employed in the treatment of bed sores attempt to treat theskin while, at the same time, strengthen the skin to prevent itsrupturing.

The present composition addresses these needs by preventing a bed sore,a reddened area of the skin, from becoming a wound, e.g., rupturing ofthe skin, by transdermally transporting nutrient active agents deepwithin the skin. This composition, moreover, acts as a further bed sorepreventative by forming a protective film over the area of the skinbeing treated. As a result, the friction between the skin and bedlinens, which precipitate the formation of bed sores, is reduced.

To effectuate these desirable treatment modes, this transdermalcomposition includes the quaternary ammonium salt in amounts effectiveto treat the skin chafing, the second reaction product amide or hydrateand the third reaction product (ether-ester) together in carriereffective amounts, as defined hereinabove. The second product or hydrateand the third reaction product transport nutrients deep into the skincross-section which prevent breakdown of the skin which cause bed soresand increase blood circulation in the affected skin area. The quaternaryammonium compound contributes to the skin treatment by forming aprotective film over the treated skin area and is present in amountssufficient to form a protective film over the treated skin area.

This composition is characterized by concentrations of the threeabove-described components such that the molar ratio of the quaternaryammonium salt to the second reaction product or amide hydrate to thethird reaction product is preferably in the range of about 1:1:1 toabout 1:15:20 and more preferably from about 1:2:3 to about 1:10:15 andeven more preferably form about 1:3:4 to about 1:6:10. Most preferablythis ratio is about 1:4:6.

A seventh transdermal composition is directed to treating skin surfaceinjuries. Skin injuries caused by cuts, skin ulcers and bruising aremanifested by primary injury to the skin surface rather than skin deepin the skin. Such injuries are therefore best treated directly at theskin surface. Indeed, components that transmit nutrients to subsurfaceskin increase blood circulation. Obviously, this is counterproductive incuts which may open and bleed, in skin ulcers which may cause pain ascapillaries suddenly are expanded by increased blood supply and burns inwhich nutrients are transported past the damaged burn surface site.

To address this unique problem of surface skin damage, this transdermalcomposition includes the quaternary ammonium salt in therapeuticallyeffective amounts for forming a protective film and the compositioncomprising the first reaction product and a monoglyceride. Thecombination of the first reaction product and the monoglyceride tend toheal wounds and do not enhance transmission of nutrients from the skinsurface. These properties in combination with the protective film formedby the quaternary ammonium salt effectively retard the flow of nutrientsto below the surface site of these types of wounds. Instead, a slow,steady flow of the requisite active agents to the surface site of thesewounds is maintained.

The three components of this seventh transdermal composition arepreferably present in a molar ratio of quaternary ammonium salt:firstreaction product:monoglyceride ranging from about 1:1:2 to about1:10:15, more preferably from about 1:2:5 to about 1:6:8 and mostpreferably 1:4:9.

In an eighth embodiment, an active ingredient may be associated with oneof the carriers, viz., the ether ester or the amide product. If theactive ingredient is to be transported to the skin but not through theskin, it is preferred that the second reaction product is the carrier.On the other hand, if the active ingredient is to transport the activeingredient through the skin, the ether-ester product can be used as thecarrier.

Alternatively, the second product or hydrate or the third product,individually or together, may comprise the carrier. They are present incarrier effective amounts.

For example, each may be combined with an antiseptic compound, such asprovidone-iodine and/or preservative, such as quaternary anti-microbialcompounds or triclosan.

These antimicrobial compounds are beneficial on the surface of the skin,but may be detrimental if in the blood stream. Accordingly, a hydrogelfor an antimicrobial is formulated comprising the second product (i.e.,amide) or hydrate as the carrier.

On the other hand, a topical analgesic compound usually may have ananalgesic active ingredient also with a broad range of nutritionalingredients. It is beneficial for the body to absorb this compound overtime. In this case, a preferred hydrogel would have both a quaternaryammonium salt, at least one film forming compound and the amide productas the carrier. Such a combination would tend to slow the rate ofabsorption.

In another embodiment, the transdermal composition comprises as theactive ingredient a whole body moisturizing crème with natural vegetableoils which is absorbed quickly. In this embodiment, the compositioncontains the amide (the second reaction product) and/or the thirdreaction product (ether-ester) as the carrier in carrier effectiveamounts in combination with the moisturizing crème in moisturizingeffective amounts in a cosmetic composition. Preferably, the aromaticamide to aliphatic molar ratio ranges from about 1 to about 6, morepreferably, from about 1 to about 4 and most preferably from about 1 toabout 3. The molar ratio of the aliphatic amide (second reactionproduct) to the third reaction product is preferably about 1:1 and morepreferably from about 1 to about 2 and most preferably about 1 to about4. In moisturizing creams, it is important to have an occlusive outerlayer. Optionally, the occlusive outer layer also include a layer thatprovide a soft silky hard feel. The occlusive layer can be a mineraloil, but it is more preferably beeswax or providone, especially PVP. Theamide is present in amounts ranging from about 0.5% to about 1.5% byweight of the composition. The second reaction product tends to emulsifyand transport the vegetable oils transdermally through the skin.

In another embodiment, the transdermal composition transports an activeingredient through the epidermis and deposits it in the dermis. Anexample of such a product is an antimicrobial moisturizing crème. Forexample, goldenseal is a natural herb that is widely used as a naturalantimicrobial compound, particularly useful against yeast. In a productdesigned to protect the bottom skin of incontinent adults, goldenseal istransported through the epidermis into the dermis. As the outer skin isworn away and sheds, the dermal skin becomes epidermal skin. Typically,the goldenseal is first implanted in the dermis, but over time, it movesto the epidermis then to the skin surface. Those skilled in the art willrecognize that any number of different compounds, natural or artificialcan be transported as goldenseal in said embodiment. However, thepresent invention is directed to the transdermal composition comprisingthe second product (amide) or hydrate in carrier effective amounts asdefined hereinabove and pharmaceutically effective amounts of thegoldenseal or equivalent. Preferably, the second reaction product(amide) or hydrate is present in an amount ranging from about 0.1% toabout 1.5% by weight of the composition, and more preferably from about0.3% to about 1% by weight of the composition and most preferably fromabout 0.5% to about 0.7% by weight of the composition. Thus, thecomposition contains the amide in carrier effective amounts. Thecomposition containing the amide permits the composition to penetratethrough the dermis.

As another example, PABA is a well known sun screen compound. Anembodiment where PABA is transported into the dermis would make aproduct that provided all day sunburn protection without recoating theskin. Such composition would contain the amide as the carrier in carriereffective amounts as defined herein and ether-ester in amountssufficient to transport the sunscreen compound to the dermis togetherwith the PABA in sunscreening effective amounts, as e.g., amounts foundin commercially available sunscreens. Preferably the amide is present inamounts ranging from about 1 to about 10% by weight of the compositionand more preferably from about 1 to about 7% by weight of thecomposition and most preferably from about 3% to about 6% by weight ofthe compositions. Preferably the amide to ether-ester molar ratio isabout 1.

The same principle works with hair. It is straightforward to envisionhair conditioner and hair colorants as being transported into the hairfollicle. Less obvious is the possibility of transporting color into theroots of the hair such that the colored hair grows out with the newcolor. The cosmetic composition of the present invention contains theether-ester and/or the amide and/or hydrate in carrier effectiveamounts, as defined here in combination with the hair conditioner inhair conditioning effective amounts, as found in hair conditioningproducts and/or hair colorants in coloring effective amounts, as e.g.,found in commercial products. Preferably the ether-ester and amideand/or hydrate are present in amounts ranging from about 3 to about 10%by weight, and more preferably from about 4 to about 7% by weight of thecomposition.

The aromatic amide or hydrate with R₇ is an anti-microbial compound.When mixed with fatty acids and soaps, a bar soap can be produced withresidual anti-microbial activity. The aromatic amide and/or hydratepenetrates the SC and binds the anti-microbial moiety to the surface ofthe skin. The anti-microbial activity remains on the skin surface untilit is naturally sloughed off. The same strategy works in a variety ofskin care products, such as antiperspirants and antiseptic hand washes.The aromatic tertiary amide (that is, a tertiary amide with R₇ present)or hydrate thereof is present in an amount ranging from about 0.1% toabout 1% by weight of the transdermal composition, and more preferablyfrom about 0.5% to about 0.7% by weight of the composition.

The aliphatic amide containing fatty groups as defined herein, orhydrate thereof is useful as a shaving cream. The tertiary amide and/orhydrate binds to the skin and leaves a protective fatty layer on thesurface. The razor glides over the surface without making nicks or cuts.

Consequently, it is preferred that the composition is prepared as shownby this exemplary procedure. It is to be noted that this procedure isillustrative.

The quaternary ammonium salt and fatty acid are placed in wateroptionally in the presence of an organic base in a mole ratio rangingfrom about 1 to about 10 and about 10 to 1 and more preferably about 1:6to about 6:1 and most preferably at about 2:1 to about 1:2 at a pH lessthan 4.5. The reaction is allowed to proceed for a proscribed length oftime for product to form (less than the time to convert the maximumamount of product). Preferably, the reaction proceeds for less than onehour and more preferably less than 30 minutes and most preferably lessthan 15 minutes. The fatty alcohol and the monoglyceride are next addedto the reaction and the mixture is allowed to stand preferably, withcontinuous stirring, for sufficient amount of time for the pH tostabilize and for the ether-ester to form. Preferably, the mixture isallowed to stand for at most 2 hours, and more preferably at most 50minutes. The molar ratio of organic base to the quaternary ammonium saltis about 0.01 to about 5, preferably about 0.5 to about 1 and morepreferably 0.06 to about 2 and most preferably from 0.07 to about 1. Thebase is added thereto and the reaction is allowed to stand until the pHstops increasing (at least about 10 minutes). Preferably, the organicbase is introduced into three separate additions. The first addition isadded concurrently with the quaternary ammonium salt wherein theviscosity is lowered so that a gel is converted to a fluid. The secondaddition of organic base is added subsequent to the completion of theformation of the ether-ester. In this procedure, gas evolution occursduring the ensuing ten minutes. When the gas evolution substantiallyceases, the amide reaction is complete. The pH of the resultant fluid isfirst increased, then slightly lowered; so a third addition of organicbase is added to raise the pH to near neutral, so that the total molarconcentration of base present after the third addition is at least equalto the amount of quaternary ammonium salt added. Other componentsnormally found in pharmaceutical compositions or cosmetics are added.Then additional organic base is optionally added in amounts effective toeffect phase stability. Then processing aids, e.g., surfactants,emulsions and the like are added and then heat labile ingredients arethen added.

Povidone iodine may additionally be added to any of the aforementionedcompositions in amounts effective to impart an anti-microbial benefit tothe compositions. Preferably, it is present in an amount ranging fromabout 3% to about 15% by weight of the composition and more preferablyfrom about 5% to about 10% by weight of the composition and mostpreferably from about 6% to about 8% by weight of the composition. It isusually added to a gel comprising the tertiary amide and the othercomponents of the composition after the gel has cooled. Then thepovidone iodine is mixed with the gel to form a stable cream.

The components of the transdermal composition of the present invention,as defined herein, when mixed in effective amounts, form emulsions. Itis to be understood that in each of the compositions of the presentinvention the components are added together in water in amountseffective to form an emulsion.

In a preferred embodiment of the present invention, the components, aremixed together to form a microsphere. The microsphere can be prepared byart recognized techniques. However, in a preferred embodiment, the fattyacid, the quaternary ammonium salt, optionally in the presence of acatalytically effective amount of the nitrogen base at a pH less than4.5 at a temperature greater than the melting point of the fatty acid,e.g. 60° C. and the active ingredient, optionally the fatty alcohol, andthe monoglycerol fatty ester and any other optional additionalcomponents found in topical pharmaceutical compositions or cosmeticcompositions are mixed together in water in amounts effective to form anemulsion, and the emulsion thus firmed is sheared under effectiveconditions to form a microsphere. More preferably, the mixture issheared with an Admix Rotosolver™ agitator (Admix, Inc. 23 LondonderryRoad, Londonderry N.H., 03053) at a shear rate greater than the CriticalShear Ratio.

Typically, when stirring a mixture containing a surfactant such as aquaternary ammonium salt, the mixture goes through a shear thinningregion at a tip speed ranging from about 50 in/sec to about 60 in/sec,wherein tip speed is calculated as the product of agitator diameter andagitator speed in revolutions per minute.

The transition is essentially linear between 50 and 60 in/sec. As thetip speed increases beyond 60 in/sec, the energy to turn the agitatorincreases. The tip speed where the shear thinning takes place is calledthe Critical Shear Rate.

Fatty mixtures of the present invention freeze at a temperature between63° C. and 55° C. That is, the fat portion of the mixture changes from aliquid to a solid across the 63-55° C. temperature range. Thistemperature range is called the Freezing Zone. Other ingredients freezeat lower temperatures.

When the mixtures of the present invention are sheared at a shear rategreater than the Critical Shear Rate as the mixture cools through theFreezing Zone, a unique structure is formed. Under a microscope, thesemicrocrystalline structures form spheres. The faster the transitionthrough the Freezing Zone, the smaller and more uniform the spherestructure.

Preferably, a quantity of ambient water sufficient to lower the mixturetemperature to a temperature just below the Freezing Zone is added as awater quench when the mixture temperature is just greater than thehighest temperature in the Freezing Zone, meanwhile mixing at a shearrate greater than the Critical Shear Rate.

More preferably, it takes about 24% of the final batch weight of 20-25°C. water to cool the mixture from 63° C. to about 53° C.

The various transdermal compositions of the present invention can beprocessed into microspheres. The microspheres contain the activeingredient. While one skilled in the art would expect small crystalsduring high shear freezing of non-fatty materials, the transdermalcompositions of the present invention surprisingly form spheres that arevisible at 1,000× magnification.

Even more surprising is the impact these small spheres have on theactive agents. For example, benzethonium chloride is the activeingredient in first aid antiseptic over the counter (OTC) products at aconcentration between about 0.1-0.2% (w/w). Benzethonium chloride is areactive material that is unstable in an acid environment; it reactswith fatty acids and soaps and thus is unstable. Thus, if added to thetransdermal compositions of the present invention which is thenprocessed into a microsphere, it would be expected that the compositionswould be unstable. However, it is just the opposite.

When benzethonium chloride is added in therapeutically effective amountsto the mixtures described herein, it is stable if added at ambienttemperature at a pH greater than 6. On the other hand, it is not stableif added at temperatures below the Freezing Zone and above ambienttemperature at a pH of about 7.5 to about 8. Surprisingly, benzethoniumchloride is stable if added at a temperature above the Freezing Zonewith a tip speed greater than the Critical Shear Rate at a pH of about7.5 to about 8.

Thus, it is advantageous to add benzethonium chloride at a temperaturegreater than the Freezing Zone because benzethonium chloride acts as apreservative against microbial growth during slow cooling to ambient.During cooling, pools of condensate accumulate on the nutrient-richsurface of the mixture. Without a functioning preservative,microorganisms can thrive at the interface between condensate andnutrient-rich mixture. With a functioning preservative, themicroorganisms are inhibited from growing.

Thus, an embodiment of the present invention comprises the varioustransdermal compositions described herein containing a preservative suchas benzethonium chloride in an amount effective to prevent or retard thegrowth of microbes processed into a microsphere, as described herein.

These transdermal compositions may additionally contain activeingredients described hereinbelow.

As one skilled in the art can well appreciate there are endless numbersof combinations that can be made to create the desired skin effects. Forexample, when the quaternary ammonium salt, such as dimethyl distearylammonium chloride (DDAC), and the like, is present in a neutral pH inthe first transdermal composition of the present invention describedhereinabove, the formic acid from the bug bite is more effectively andmore rapidly neutralized. On the other hand, when the quaternaryammonium salt, e.g., DDAC, is present in the seventh transdermalcomposition of the present invention, the healing rate on open woundsimproves. However, when the quaternary ammonium salt, e.g., DDAC, is notsubstantially converted to the first reaction product, some of thepatients, approximately 25% thereof, feel pain. But, when the quaternaryammonium salt, e.g., DDAC, is split between the first reaction product(80%) and the unreacted DDAC (20%), rapid healing is observed and thepatients did not feel pain.

If cetyl alcohol is additionally present, when it is present in the acidreaction zones, the pain is mitigated, however, when present in theneutral zone the detergency of the formulation increases.

Another embodiment of the present invention relates to a combinationproduct, i.e., compositions containing one or more of the following: thequaternary ammonium salt, fatty acid, fatty alcohol, nitrogenous base,monoglycerides, the first reaction product, the second reaction product,the third reaction product and the fourth reaction product. Examples ofthese are exemplified in Examples 17-24. It is preferred that suchcombinations include at least one of the carriers described hereinabove.

In an example, these combination products can be used as a moisturizingskin product and barrier product, as for example, in maintaining skinhealth.

Maintaining skin health is always complex, particularly with hands thatare exposed to harsh chemicals. For example, health care workers andworkers in the food manufacturing and food handling business are alwayswashing their hands and sanitizing with iodine or >62% alcohol.Treatment with antiseptic products tends to cause cracking and chaffingof hands (contact dermatitis). Hands that are cracked can harbormicroorganisms in the cracks. It is difficult to kill these hiddenmicroorganisms because the antiseptic fluids cannot get into the cracksand crevices during the sanitizing process. Thus the hands emerge fromthe sanitizing process with viable organisms which can grow out tomeaningful populations between sanitizing treatments.

Other workers use their hands with aggressive chemicals. Workers in thechemical industry and workers in the beauty care industry stress thehealth of their skin by handling the normal chemicals inherent in doingtheir job. These hands are often cracked and chapped. The antisepticnature of the hands is typically not critical, but cracked and chappedhands hurt. This is particularly true for beauty care workers whosemotor skills are crucial to their jobs.

Ingredients that are necessary for healthy hands should be rapidlyabsorbed by the skin. Antiseptic ingredients should not be absorbed bythe skin. A barrier product to keep noxious chemicals away from the skinshould not be absorbed.

It is difficult to make a skin care product that is simultaneouslyabsorbing and not absorbing. In a situation where the skin requires anabsorbing technology and a non absorbing technology, more than oneapplication is required.

The prior art deals with this problem by using a moisturizing crèmefollowed by an antiseptic or a barrier crème. This solution can make thehands feel better, but the secondary treatment of either sanitizing orproviding a barrier is compromised because the moisturizing ingredientsin the first application remain on the surface of the skin. The surfaceoils cover and protect the microorganisms, such that the expectedsanitizing is compromised.

Likewise with a barrier crème, the barrier cannot attach to the skinbecause there is an intermediate level of moisturizing oil between theskin and the barrier.

This dilemma is solved by having a transdermal first application. With amixture such as the fourth transdermal composition described hereincontaining nutrients, as disclosed herein, especially olive oil,(preferably about 5.3%), the composition is transdermally delivered tothe subsurface skin. Along with other transdermal nutrients, theinterior skin is fed and strengthened. Importantly, the surface issubstantially dry and prepared for a second application.

In an embodiment, the second application is the antiseptic mixturepreviously disclosed hereinabove.

In another embodiment, barrier film forming compounds are added to theseventh transdermal composition, as described herein. A preferredembodiment is exemplified in Example 20 hereinbelow, except that CetylAlcohol is 3.82%. Furthermore, said barrier film compounds are added inamounts effective to form a barrier film, said barrier film formingcompounds are added after the quench water has dropped the temperaturebelow the Freezing Zone in the formation of the microspheres. Thistechnique removes the barrier compounds from the microcrystalline sphereformation.

Examples of barrier film forming compounds are:

Waxenol 822—arachidyl behenate, Polyderm PE—poly diethyleneglycoladipate/IPDI copolymer, Polyderm CO—castor oil/IPDI copolymer, MonodermI-20—octyl dodecanol dimer with IPDI, Polyderm SA—dimethiconol DI-PEG 2soyamine/IPDI copolymer, Monoderm I-16—isocetyl alcohol dimer with IPDI,all of which are sold by Alzo international, Inc.

The barrier mixture can be used alone or as a second product following atransdermal moisturizing treatment.

One skilled in the art will recognize that alternate barrier compoundsare possible as well as varying the relative amounts of the listedbarrier compounds. In the present invention, the skin is protected usinga transdermal composition followed by a non transdermal composition.

The transdermal compositions of the present inventions can be apharmaceutical composition or cosmetic composition. The topicalcompositions may be in a number of common forms typically of topicalformulations, e.g., hydrophilic lotion, an ointment, cream, gel, sprays,salves, jellies, pastes, syrups and the like. They may include one ormore other formulation additives typically found in cosmetic orpharmaceutical compositions.

It is preferred that the transdermal compositions are provided with aliquid carrier although they may be carrier free. This liquid carrier isany liquid which the liquid carrier for the composition can also vary.Indeed, any carrier that does not substantially interfere with thecomponents or the function of the components, and which allows a film toform and thereby exclude the carrier from the skin surface as itevaporates, is suitable. Exemplary carriers include water, and lowermolecular weight alcohols such as ethanol, isopropyl alcohol, sec-butylalcohol, glycerin, and propylene glycol, although water is generallypreferred for the particular ingredients described in this document.Alternatively, the carrier may be one of the carriers identifiedhereinabove. In another embodiment, the carrier may be a combination ofany of the above.

The composition may comprise one or more active agents, which are chosenbased upon the properties that one desires from the composition. Forexample, in one embodiment the composition may include an aggressivecleansing or skin preparation ingredient. Such active agents cleanse thesurface of the skin immediately upon application of the composition tothe skin, and cleanse the skin sufficiently before a film is formed fromthe first film forming component, and before the first film formingcomponent excludes the active agents from the surface of the skin.

As an active agent the composition may contain cleansing ingredientscapable of removing microbials, viruses, and other foreign contaminantsfrom the surface of the skin. Cleansing ingredients may also be capableof scouring dead and dying layers of skin from the skin surface. Thecleansing ingredient may suitably comprise non-ionic surfactantsbecause: (1) this class of compounds readily cleanses the skin, andremoves the fatty dead, and dying layers of the outer surface of theskin (the stratum disjunction and stratum corneum); (2) this class ofcompounds is typically very soluble in the water base of thecomposition; (3) this type of compound is an effective antiviralcompound; and (4) this class of compounds allows the proper functioningof the other active ingredients of the composition.

Surfactants may also be present as a processing and/or as active agent.As an active agent, they are particularly suitable because of theirability to cleanse at the interface of the liquid composition and theouter layers of the skin. A particularly suitable nonionic surfactant issold under the trademark Triton X-100, and comprises octoxylenol, mostsuitably having 9-10 repeating units of ethoxylation. Anotherparticularly suitable nonionic surfactant is nonoxynol-9, which can beused alone or in combination with other surfactants.

Suitable anti-microbial and cleaning active agents that can be used asactive agents or as additions can be incorporated into the compositioninclude propylene glycol, berberine sulfate, various quaternary ammoniumcompounds, such as dimethyl benzethonium chloride, benzalkoniumchloride, benzethonium chloride, and cetyl pyridinium chloride.Additional antimicrobial and cleansing agents include, but not limitedto parachlorometaxylenol, nonoxynol-9, chlorohexadine gluconate, andlauricidin (glycerol monolaurate). Other active agents include skinhealing emollient ingredients such as allantoin, aloe, dimethyl sulfone,dimethicone, fragrances and anti-oxidants.

It is also possible to include active agents with medicinal propertiesin the composition which, when delivered topically, are absorbed by theskin and metabolized. Any active agent that is fat or water soluble, orwhich can be rendered fat or water soluble, is a suitable candidate fordelivery through the compositions of the present invention, because suchagents are capable of migrating through the final film formed by thecomposition, and thereafter being topically delivered to the skin.

An example thereof is the transdermal composition of the presentinvention in association with a herb, such as the fourth transdermalcomposition described hereinabove. The herb may be present as a completeextract or a fraction thereof. Many herbs are functional activeingredients, but are digested when entering the body via the stomach.However, when the active herbal extracts are delivered to the skintopically in association with a transdermal composition of the presentinvention, the herb can act on the targeted site on the skin, withoutbeing digested. For example, when the herb extracts is present in thetransdermal composition of the present invention, it was effective intreating skin cancer if present in cancer treating effective amounts,retarding the growth of the cancer cells or killing the cancer cells.

The medicinally active agents of the invention can be added singly, orin any combination. Each medicinally active agent typically comprisesfrom about 0.01 weight % to about 95% and more preferably about 30weight percent of the composition, although active agents can bepresent, either singly or in combination, in quantities as high as about35 wt. %, about 20 wt. %, about 15 wt. %, about 1.0 wt. %, or about 5wt. %. Most medicinally active agents as defined by the FDA arepreferably present from about 0.01 weight % to about 5:0 weight percent.Preferred medicinally active agents, not defined by the FDA, includealkylglycerols, alkoxyglycerols, polyunsaturated fatty acids orpolyunsaturated oils, fat soluble vitamins, sulfur compounds, minerals,antioxidants, amino acids, energy stimulators, steroidal hormones, orglycoprotein hormones. Preferred medicinally active agents also includea variety of other healing agents including glycyrrhizic acid,ribonucleic acids, aloe vera, allantoin, bioperine, berberinehydrochloride, colostrum, dexpanthenol, glucosamine salts, inositol,phytantriol, pyrrolidine carboxylic acid, jojoba oil, symphytumofficinal, polysorbate 80, vanilla extract, and adducts of a nitrogenousorganic base and a fatty acid. Adducts of nitrogenous organic bases andfatty acids are especially appropriate for use in higher concentrations.

Glycerides, including mono-, di-, and triglycerides, and alkoxyglycerolsand alkylglycerols, are particularly suitable as active agents, or ascarriers for active agents, in topical applications. These componentshave independent medicinal properties, are capable of independentlymigrating through the film, and can also solubilize other fat solubleactive agents and carry them through the first film to the surface ofthe skin, Particularly suitable glycerides typically comprise from about10 to about 36 carbon atoms, can be conjugated or saturated, and aregenerally liquid at room temperature. Preferred glycerides include,lauricidin, vitamin D suspended in palm oil, conjugated linoleic acid(“CLA”), gamma linolenic acid (“GLA”), and eicosapentaenoic acid (EPA).Highly unsaturated oils are also especially suitable active agents insuch topical applications because such oils have an antioxidant benefitwhen applied to the skin, and in addition they are effective transportvehicles for fat soluble active agents.

The polyunsaturated fatty acids used as medicinally active agentsinclude conjugated linolenic acid, alpha-linolenic acid, alpha-linoleicacid, gamma linolenic acid, dihomo-gamma-linolenic acid, docosahexaenoicacid, eicosapentaenoic acid. The polyunsatured fatty oils useful in theinvention include neem oil, shark liver oil, lemon oil, or squalene.Other fatty oils include lemon oil and squalane. Shark liver oil and/orneem oil are typically used at higher concentrations than othermedicinally active agents, and are thus typically present atconcentrations of up to 10, 5, or 3 wt. % of the composition.

Preferred fat soluble vitamins include vitamin A, vitamin D, vitamin E,vitamin K, a tocotrienol, lycopene, b-carotene, ascorbyl palmitate, andluteine. Preferred sulfur compounds include dimethylsulfone, zincsulfate, or lipoic acid. Preferred minerals include zinc sulfate; zincl-monomethionine; and compounds of copper, calcium, magnesium, chromium,selenium, vanadium, cobalt, and silica. Compounds include salts andchelates, among others, and especially include calcium proprionate;copper porphyrin compounds, silicic acid or silica gel, andcopper-curcumin.

Preferred anti-oxidants include ascorbyl palmitate, neem oil, squalene,ferulic acid, lipoic acid, grape seed extract, boswellin, and bilberryextract. Preferred amino acids include arginine, proline, glutamine,glycine, or trimethyl glycine, ornithine alpha-ketoglutarate, and1-pyrroglutamic acid.

Energy stimulators may also be active agent. These are defined ascompounds that provide easily metabolized sources of energy for thesynthesis of ATP, and include bee pollen, natural honey, forskholin, andarginine. Preferred steroid hormones include cortisol, pregnenolone, anddehydroepiandrosterone.

Another class of active agents include optically fluorescent orphosphorescent compounds or compositions that can absorb ultravioletlight and re-emit it as visible light. When hands or other skin surfacesthat have been treated with the resulting fluorescent or phosphorescentcompositions, exposure to a source of ultraviolet (“black”) light can beused as a method to check for the presence of the composition on theskin. This property might be particularly useful in skin cleaning and/orskin protecting compositions utilized in hospital, food manufacturing,or food service facilities, as a means for easily checking for thepresence of the cleaning or skin protecting composition.

As stated above, the transdermal compositions of the present inventioninclude new components that are new compounds. The first of these is thecompound which is the reaction product of a quaternary ammonium compoundand a fatty acid. This reaction occurs in an aqueous solvent at atemperature greater than the inciting point temperature of thequaternary ammonium compound over a time period long enough for thereaction mixture to reach a substantially constant pH which pH is lessthat the pH of any single reactant present in the reaction mixture whenmeasured alone in water.

An example of this reaction to produce the new compound, dimethyldistearyl ammonium stearate, involves reaction of the quaternaryammonium compound, dimethyl distearyl ammonium chloride, with the fattyacid, stearic acid, infra.

A second new compound employed in the transdermal compositions of thepresent application is the reaction of the first reaction product with acatalytically effective amount of nitrogenous organic base. This classof new compounds is illustrated by the reaction of dimethyl distearylammonium stearate in the presence of an effective amount of nitrogenousorganic base, e.g., triethanolamine, wherein the reaction occurs at theconditions present at the time when the first reaction product wasformed. This reaction product is an amide.

A third new compound is denoted as the third reaction product. Thatproduct is the reaction product of a first reaction between a fatty acidand a fatty alcohol in acid to film a fatty ester and a second reactionbetween the fatty ester and a monoglyceride. An example of that newcompound is the product formed by the stepwise reaction of the fattyalcohol, e.g., cetyl alcohol, and the fatty acid, e.g., stearic acid,and then the monoglyceride, glycerol monolaurate. This reaction, whichoccurs under acidic conditions, produces the reaction product compoundcetyl glycerol laurate.

The various transdermal compositions described herein are appliedtopically to the skin of a patient. In the present invention, thepatients to whom the transdermal applications are applied are mammals.Examples of mammals who can benefit from application of the transdermalcompositions thereto include dog, cat, horse, pig, cow, donkey, monkey,humans, and the like. The most preferred mammal is human.

It is to be understood that the transdermal compositions of the presentinvention are applied topically to the skin. Moreover, the transdermalcompositions of the present invention may be carrier free, although itis preferred that a carrier typically used in the pharmaceutical arts orcosmetic arts or a carrier described hereinabove, such as the secondreaction product or third reaction product or fourth reaction product,be the carrier associated with the pharmaceutical agent.

The present invention includes kits which encompasses the aforementionedtransdermal compositions, and portions thereof. That is, kits within thescope of the present invention comprise complete components of each ofthe transdermal compositions, components that comprise the compositionswithout the active agents and/or liquid carriers and the like. Forexample, the kit may contain one container containing the carriersidentified herein and the other container containing the active agent.

As used herein, the plural denotes the singular and vice versa. Unlessindicated for the contrary, the percentages are by weight.

In addition, the term “saturated” and “unsaturated” refers to the numberof carbon-carbon double bonds. If a fatty acid or alcohol is saturatedor completely saturated, this denotes that the fatty acid or alcoholcontain no carbon-carbon double bonds; if on the other hand, the fattyacid or alcohol is unsaturated then it is to be understood that itcontains at least 1 carbon-carbon double bond.

The abbreviation TEA refers to triethanolamine.

Moreover, unless indicated to the contrary, the term “amide” refers tothe second product, or hydrate as defined herein.

Further, unless indicated to the contrary, the term salts of a fattyacid or synonym thereto refers to a pharmaceutically or cosmeticallyacceptable salt thereof.

As used herein, the term aliphatic tertiary amide or aliphaticquaternary salts or equivalents thereto refers to tertiary amide orsalt, respectively containing only aliphatic moieties thereon in theabsence of aromatic moieties.

The term aromatic tertiary amides or aromatic quaternary salts orequivalents thereto refers to a tertiary amide or quaternary saltrespectively, which has at least one group thereon containing an arylmoiety as defined herein, e.g., aryl group, aryl alkyl group or R₇.

The term treating refers to management and care of a mammalian subjectfor the purpose of combating disease, condition or disorder byadministering a pharmaceutical composition as defined herein topicallyto the skin, and promoting the healing thereof or alleviation of thesymptoms associated with the disease, condition or disorder.

The process for making tertiary amides is illustrated in the Examplesand is now described generically:

1. Water, quaternary surfactant and fatty acid are heated together at atemperature greater than the melting point of the fatty acid with gentlestirring for a time long enough to enable gas to form and dissipate. ThepH drops below the pH of either component-in-water alone before the gasrelease occurs. Optionally, small amounts of nitrogenous base, e.g., TEAcan be added such that the resulting pH is less than about 6. Base, suchas TEA reduces the tendency to form gels. Too much base, e.g., TEAraises the pH above 6.

2. The pH of the mixture can be rapidly increased by the addition of abase. The rate of pH-increase is reduced significantly when thebase-to-fatty acid molar ratio is greater than 1 (which excessquaternary surfactant). The rate of pH-increase is reduced significantlywhen the base-to-quaternary molar surfactant ratio is greater than 1(with excess fatty acid). The rate limiting component defines theinflection point where the rate of pH-increase slows.

3. Aliphatic quaternary surfactants mixed with fatty acids release gasmore slowly than aromatic quaternary surfactants and are more likely toform gels. Gel formation inhibits gas release. High shear mixing in thepresence of released-not-yet-dissipated gas forms gels that inhibit gasrelease. Aliphatic quaternary surfactants and fatty acid do not releasegas at a pH greater than about 6.

4. A particularly effective way to prevent gel formation is to addquaternary surfactant to fatty acid in steps. The gas release beginsafter the first step, then dissipates. The nest step of quaternarysurfactant is added, a weak gel may be formed, but more gas is releasedand dissipates. The gel breaks when the gas is dissipated. The totalabout of gas release is greater when partial quaternary surfactantadditions ate made slowly rather than adding all the quaternarysurfactant at once.

5. If a gel forms a gas release substantially stops, the gbas releasecan be restarted by diluting the reaction mix with water. The optimumgas release temperature is about 80±10° C. Gas release time foraliphatic quaternary surfactants is about 60 minutes @80° C. Gas releasetime for aromatic quaternary surfactants is about 30 minutes @80° C. Ifthe fatty acid is in molar excess, the gas release is faster. If thequaternary surfactant is in molar excess, gels may form. Aliphaticquaternary surfactants are more likely to form gels than aromaticquaternary surfactants.

6. Aromatic quaternary surfactants, mixed with fatty acids at a pHgreater than 6, release gas. The rate of release is slower at higher pH.The ideal pH is less than 4.5. The gas release takes place at ambienttemperature if the fatty acid is liquid at ambient temperature.

7. Aromatic quaternary surfactants will release gas with unsaturatedfatty acids in the present of an assortment of other compounds;aliphatic quaternary surfactants do not release gas when mixed with, forexample, calcium-containing compounds. For example, in Example 20, ifthe benzethonium chloride is added at a temperature less than thefreezing point of the saturated fatty acid (e.g. <55° C.0₃ the is animmediate rise in the level of the processing vessel and an endothermictemperature drop. It is believed that the benzethonium chloride isendothermically reacting with the various unsaturated fatty acids andreleasing gas (the saturated fatty acids cannot react because thetemperature is less than the freezing point of said saturated fattyacids; the release gas is entrained and reduces the specific gravity ofthe mix). Example 20 contains aloe, a calcium-containing compound.

8. When the fatty acid and quaternary surfactant are first heated inwater, the pH drops below 5. If fatty alcohol and glycerol esters aremixed together, the pH rises and falls cyclically. After about one hour@80° C., the pH fluctuation substantially stops.

The following non-limiting examples further illustrate the presentinvention.

Example 1 Formation of Distearyl Stearamide and Cetyl Glycerol Laurate

An equimolar mixture of stearic acid and dimethyl distearyl ammoniumchloride (DDAC) was dissolved in water in the presence oftriethanolamine (TEA) wherein the TEA was present such that the moleratio of DDAC to TEA was 10:1. The aqueous mixture was maintained at atemperature in excess of 60° C. and at a pH in the range of from about 3to about 5.

The reaction proceeded with the evolution of gas. The pH of the reactionmixture was measured during this reaction. The pH dropped exponentiallyfrom a pH in the range of 5 to 6 down to a pH of 2 to 3 within 5minutes. This is quite remarkable insofar as the pH of stearic acid inwater is about 4.5 and the pH of DDAC is about 6.

Cetyl alcohol and glycerol monolaurate were thereupon added to thereaction mixture in a concentration of 4 moles of each of thesecompounds per mole of DDAC. Gellation and subsequent creaminessoccurred. The reaction mixture was unchanged for 75 minutes. Subsequentto the aforementioned 75 minute reaction time, TEA was added in anidentical concentration as the first addition of TEA, that is, one moleof TEA was added to the reaction mixture for every 10 moles of DDACpresent therein. The second addition of TEA resulted in further gasevolution. This reaction was allowed to continue for 10 minutes.

A third charge of TEA was introduced into the reaction mixture to bringthe total TEA concentration equal to the molar concentration of the DDACto bring the total such that the pH of the reaction was greater than 6.

The reaction was stopped by addition of the dimethylation inhibitor,aloe vera (0.25%, by weight based on total reaction mixture).

Example 2 Formation of Dimethyl Distearyl Ammonium Stearate (DDAS) andCetyl Glycerol Laurate

Example 1 was repeated but for the absence of TEA from the equimolarmixture of stearic acid and DDAC and from the addition of cetyl alcoholand glycerol monolaurate. Instead, an amount of TEA, equal to the totalamount added in Example 1, was added at the time of additions of TEA inthe third charge in Example 1.

Example 2A Formation of DDAS and Cetyl Stearate

Example 2 was repeated but for the sequence of addition of glycerolmonolaurate. Instead of being added with cetyl alcohol, an equal amountof glycerol monolaurate utilized in Example 2 was added after theaddition of the TEA.

Example 2B Formation of DDAS and Triethanolamine Stearate (TEAS)

Example 2A was repeated but for the sequence of addition of glycerolmonolaurate and cetyl alcohol. Instead of being added in the secondstep, after the equimolar mixture of stearic acid and DDAC, the sameamount of the glycerol monolaurate and cetyl alcohol added in Example 2was added after the addition of TEA.

Example 2C Formation of DDAC and TEAS

Example 2B was repeated but for the addition of DDAC prior to additionof TEA. Rather, an equal amount of DDAC added in Example 2B, was addedconcurrently with the addition of glycerol, monolaurate and cetylalcohol.

Example 2D Formation of Distearyl Stearamide (DSS) and Cetyl Stearate

Example 1 was repeated for both the sequence of addition of glycerolmonolaurate. The glycerol monolaurate added in Example 1 concurrentlywith cetyl alcohol, was added subsequently to the third addition of TEA.

Example 2E Formation of DSS, Cetyl Glycerol Laurate and Cetyl Stearate

Example 1 was repeated but for the mole ratio of stearic acid and DDAC.Whereas the mole ratio of stearic acid to DDAC in Example 1 was 1:1, themole ratio of stearic acid to DDAC was 2:1. In addition, the molar ratioof glycerol monolaurate to cetyl alcohol, which was 1:1 in Example 1,was 0.5:1.

Example 2F Formation of DSS, Cetyl Glycerol Laurate and TEAS

The process of Example 1 was repeated but for the inclusion ofadditional stearic acid. The stearic acid which was added subsequent tothird introduction of TEA resulted in a molar ratio of stearic acid toDDAC of 2:1.

Example 2G

The process of Example 1 was repeated, except that 0.5% aloe vera wasadded with the DDAC and the TEA.

Examples 3-5 Preparation of Transdermal Compositions Employing VariousFatty Acids

Example 2 was repeated employing the fatty acids; Conjugated LinoleicAcid (CLA); eicosapentaenoic acid (EPA); and gamma linolenic acid (GLA),were all dissolved in water and the pH of the resulting solutions weremeasured with a calibrated pH meter. These pH's are reported in Table 1.

Three solutions of DDAC (188.2 g) in distilled water (2,000 g) werecontacted with masses of CLA, EPA and GLA, such that the molar ratio ofDDAC to each of the aforementioned fatty acids was 1:1 at a temperatureof 70° C. to 75° C. and after 10 minutes the pH of the reaction productsof each of these products was measured. These results are summarized inTable 1.

TABLE 1 Reaction of Quaternary Compound Example Quaternary with FattyProduct No. Compd, g pH Acid, g (pH) Compound pH 1 DDAC, 188.2 5.38 None2 DDAC, 188.2 5.38 Stearic, DDAS 2.38 80 g (4.81) 3 DDAC, 188.2 5.38CLA, Dimethyl 2.28 (4.00) Distearyl Ammonium Linolenate (DDAL)

Examples 6-9 Preparation of First and Second Transdermal CompositionsEmploying Various Quaternary Compounds

Four quaternary compounds, dimethyl benzethonium chloride (DMBC) (27 g),monomethyl benzethonium chloride (MMBC)(19 g), benzalkonium chloride(BAC) (50 g) and Merquat 550 (96 g) were mixed with distilled water(2,000 g), Merquat 550 is a trademark owned by Calgon, Inc. itsmanufacturer, for a proprietary cationic polymer having a repeating unitmolecular weight of 680 and an overall molecular weight of about 10,000.The pH of these first transdermal compositions were measured. Thesolutions were thereupon heated to 70°-75° C. and stearic acid (40 g)was added. Ten minutes after acid addition, the pH of the productcomposition were measured. The results of these examples are summarizedin Table 2,

TABLE 2 Quaternary pH of Quat and Compound pH Stearic Acid DMBC 5.023.01 MMBC 4.47 2.32 BAC 7.83 2.40

Example 10

DDAC (89 g) was mixed with distilled water (2,000 g) and heated to 50°C. in a 6-quart double boiler with continuous stirring. Melted stearicacid (82 g) was added and the mixture was heated to 70° C.-75° C. for 20minutes. Melted cetyl alcohol (105 g) was thereupon added to the mixtureat 70° C.-75° C. and the mixture remained heated at 70° C.-75° C. for anadditional 20 minutes % Glycerol monolaurate (79 g) was added and themixture was heated for 20 more minutes at 70° C.-75° C. Triethanolamine(TEA) was added in an amount of 0.1 wt %, based on the total weight ofthe mixture, every minute. The pH of the mixture was measured after eachaddition of TEA.

The mole ratio of the compounds, adjusted for the purity in the rawmaterial, specifically, stearic acid to DDAC to cetyl alcohol toglycerol monolaurate to TEA was 1:0.5:1.5:1:2, respectively.

The of the reaction from the beginning of the experiment as a functionof time, where 0 time represents the time of initial addition of TEA,and wherein initial addition of cetyl alcohol, glycerol monolaurate andthe point where the molar concentration of TEA reaches the molarconcentration of DDAC are provided thereon as set forth in FIG. 1.

Analysis of Example 10

A review of FIG. 1 demonstrates that the pH of distilled water, 5.2immediately drops after addition of stearic acid at 50° C. to about 2.36upon reaction of DDAC therewith. This reaction generates hydrochloricacid resulting in this pH reduction. The pH then increases from 2.33 toabout 2.60 upon addition of cetyl alcohol as it reacts with stearicacid. The fatty ester product of this reaction is reacted with glycerolmonolaurate, a glycerol mono fatty ester resulting in a drop of pH fromabout 2.48 to about 2.23 insofar as this reaction effects in theregeneration of stearic acid as well as the concurrent formation ofcetyl glycerol laurate. The pH rapidly rises from about 2.26 to about6.0 as TEA is introduced. This steep increase in pH ceases at theinflection point when the molar concentration of TEA equals theconcentration of DDAC, which is equal to the number of moles ofhydrochloric acid generated in the reaction of DDAC with stearic acid.The slower increase in pH is a manifestation of further addition of TEA.

The two different slopes of rising pH represents the neutralization ofstrong acid by TEA followed by the buffering effect of the reactionmixture by TEA and DDAS.

Example 11

Distilled water (2000 g) was mixed with DDAC (1% to 10% by wt.) andheated to 50° C. in a 6 quart double boiler with continuous stirring.Stearic acid (82 g) was added to the mixture and heated to 70° C. to 75°C. for 10 minutes. TEA was added at a rate of about 2 g/min. The pH wasmeasured every minute. This data was plotted as in FIG. 1 depicting thedata of Example 10. The inflection point between rapid and slow pH wasstatistically determined. These results are set forth in Table 3,

TABLE 3 TEA, g Prior to DDAS/TEA Mole Ratio at Wt. % DDAC Inflection Pt.Inflection Point 1 6 0.9 2 10 1.08 4 21 1.03 6 31 1.04 8 39 1.11 10 331.63

Analysis of Example 11

The number of grams of TEA added prior to reaching the inflection pointincreased linearly when the wt % DDAC increased from 2 to 8 wt %. Themole ratio of DDAS/TEA averaged 1.06 over this range establishing thatthe conversion of DDAC to DDAS, when DDAC was reacted with stearic acid,was almost complete during the 10 minute reaction period.

Example 12

Distilled water (1,245 g) and DDAC (178 g) was heated to 50° C. in a 6quart double boiler with continuous stirring. Melted stearic acid (164g) was added to the distilled water. The resultant mixture was heated to70° C. to 75° C. for 10 minutes. The pH dropped from 5.59 to 2.56.Melted cetyl alcohol (140 g) was added to the mixture at 70° C. to 75°C. and maintained at this temperature for 10 minutes. The pH increasedfrom 2.56 to 2.62 as this reaction proceeded. Glycerol monolaurate (79g) was added to the mixture at 70° C. to 75° C. The pH decreased from2.62 to 2.40. During this pH reduction an additional amount of glycerolmonolaurate (79 g) was added, with crude beeswax (24 g), propolis (1 g)and CLA (17 g), to the reaction mixture during the next 5 minutes. Therate of pH decline was unchanged during this period.

TEA (8.7 g) was added resulting in a pH increase to 3.5. However, the pHdeclined to about 3.0 over the next 20 minutes white the temperature wasmaintained at 70° C.-75° C. Tiny foam bubbles were noticed beingreleased from the stirred mixture. It is theorized that these bubblesrepresent the release of methanol.

The pH response to this experiment is depicted in FIG. 2 wherein pH ofthe mixture is depicted as a function of time. The response subsequentto addition of 0.1 mole TEA per mole of stearic acid is depicted in FIG.2 as a converging harmonic decay. The viscosity of the mixture alsodropped dramatically after TEA addition. This response is theorized tobe the result of a converging harmonic decay due to competing reactionsdriven by the loss of stearic acid as cetyl stearate is formed (pHrises) and the gain of stearic acid as the cetyl stearate reacts withthe glycerol monolaurate and regenerates stearic acid (pH falls). The pHeffect from the two interdependent reactions oscillates back and forth,as first one reaction and then the other one predominates. As thereagents are consumed, the range of fluctuation declines when all thecetyl stearate and all of the glycerol monolaurate reactions aresubstantially complete and the is stabilized. That is, the reaction ofDDAC and stearic acid, as well as the reaction of cetyl glycerol laurateand cetyl stearate, generate acid resulting in lower pH. The reaction ofTEA with protons to form protonated TEA and the reaction of cetylalcohol and stearic acid to form cetyl stearate both increase pH. Assuch, pH fluctuates. As the reactions go to completion, the fluctuationsin pH are reduced. When the reactions are substantially complete the pHis stabilized.

When the pH was stable, distilled water (623 g) was added at 70° C. Asillustrated in FIG. 2, no inflection point was observed. Instead, afteronly 5 additional grams of TEA were added, the pH gradually rose. Thisincreased pH continued until 51 grams of TEA were added at a rate of 2g/min. All the remaining TEA was thereupon added all at once to yield afinal pH of 7.83.

Propylene glycol (3.5%) was added at 70° C. and Carbomer (0.5%) wasadded at 68° C. At 65° C., additional distilled water (623 g at 25° C.)was added. Agitation was increased until a smooth hand cream wasobtained. Upon cooling to ambient temperature, a trained panel describedthe product as “drying”. This drying effect was deemed the result of theformation of the tertiary amide and its partial penetration of the SC inthe absence of an occlusive layer, such as beeswax or mineral oil.Tertiary amides open the pores of the skin, allowing moisture to leavethe surface of the SC. An occlusion layer on top of the tertiary amidelayer retains moisture.

Example 13

in this example, all reactions occurred simultaneously. That is, thereactants: distilled water (2,000 g); DDAC (178 g), stearic acid (164g); TEA (8.6 g); glycerol monolaurate (79 g); and cetyl alcohol (140 g)were added at ambient temperature to a 6 quart double boiler. TEA (8.6g), however, added so that the molar ratio of TEA to stearic acid was0.2:1, occurred before the addition of the glycerol monolaurate andcetyl alcohol.

The undissolved unmelted TEA-containing mixture was heated, withcontinuous stirring at 70° C. The pH response was an exponential decaywith a slight drop in pH to about 3.12. After the reaction was allowedto react for 70 minutes, TEA was added at a rate of about 0.5 gram perminute until 9.7 gams were added. This addition is depicted in FIG. 3wherein pH is shown as a function of TEA added. The pH response waslinear up to a pH of 3.85 followed by a step increase to 4.44 coincidingwith a physical phase change. Subsequent to the phase change, glycerolmonolaurate (79 g), propolis (1 g), crude beeswax (24 g) and CLA (17 g)was melted and added to the double boiler along with water (623 g at 70°C.) and heated for 5 minutes. TEA (40 g) was added at a rate of 2 g/min.Additional TEA, to bring the total amount to 341 grams, was added at onetime. Propylene glycol (160 g) was added at 70° C., Carbomer, e.g.,Carbomer 980 (16 g), a trademark for a polyacrylic acid, owned by B.F.Goodrich, was added at 68° C. The mixture was subjected to highagitation at 65° C. to shear and smooth the emulsion.

The resulting salve, after being cooled to ambient temperature, wasjudged by trained panelists to be Moisturizing. Glycerol monolaurateadded to the acid reaction was equal to the molar amount of availablecetyl alcohol. Glycerol monolaurate, added after the neutralizationphase change, which occurred at a pH of 4.44, did not react withpreexisting cetyl stearate. As a result, there was no free stearic acidto react with TEA and thus no TEA:stearate formed. The absence of aninflection point, as seen in FIG. 3, indicated that there was no strongacid to neutralize.

Products obtainable from variations in relative ratios and time ofaddition of components of Example 13 are summarized in Table 4.

TABLE 4 Trans- Mois- Skin Pro- Topical Anti- dermal, turizer, tectant,Analgesic, septic, Reactants Moles Moles Moles Moles Moles Stearic Acid1 1 1 1 1 (@0.89 (@0.889 (@2.05 (@4.1 (@3.75 wt %) wt %) wt %) wt %) wt%) DDAC 1 1 1 0.5 0.16 Glycerol 4 4 1.5 0.59 0 Monolaurate¹ Glycerol 0 00.25 0.32 0.96 Monolaurate² Cetyl Alcohol 4 4 1.5 1.09 0.84 Triethanol-0 0.2 0.2 0.2 0.2 amine¹ Trans- dermal Mois- Skin Pro- Topical Anti-Device, turizer, tectant, Analgesic, septic, Products Moles Moles MolesMoles Moles DDAS 1 0 0 0 0 Distearyl 0 1 1 0.5 0.16 Stearamide CetylGlycerol 4 4 1.5 0.59 0 laurate Cetyl Stearate 0 0 0 0.5 0.84 TEAStearate 0 0 0 0 0 Stearic Acid 0 0 0 0 0 DDAC 0 0 0 0 0 Glycerol 0 00.25 0.32 0.96 Monolaurate Cetyl Alcohol 0 0 0 0 0 ¹In acid mixture ²Inneutral mixture

The five compositions decrease in conveyability through the skin surfacefrom complete transmittability in the transdermal composition to totalnon-absorptivity in the antiseptic composition.

Example 14

A composition in accordance with the moisturizer embodiment of Example13 was prepared. That is, a two-step process was followed in whichacidic compounds were first neutralized and then the system wasstabilized.

In the first step, the specific components, with their concentration inpercentage by weight, based on the total weight of the moisturizer,noted, were provided: distilled water, 13.8%; DDAC, 1.9%; stearic acid,0.89%; cetyl alcohol, 3.1%; and glycerol monolaurate, 2.35%. Thesecomponents were heated under continuous stirring at 70° C. for 30minutes. TEA, 3.45%, was thereupon added at one time and the mass wasmixed until a hard solid formed. Ambient temperature distilled water,4.13%, was then added at ambient temperature and mixed until a smoothmass was obtained.

A separate mass, which comprised the following components, with theirconcentration indicated, were combined: distilled water, 4.13%,allantoin, 0.4%, aloe vera, 0.25%; and Dimethyl sulfone (MSM), 1%. Thismass was heated to 70° C. whereupon the following components were added:propylene glycol, 1.5%; glycerin, 3.5%; lemon oil, 0.4%; vanilla, 0.1%;and olive oil, 2.0%. This second mixture was cooled to 65° C. andCarbomer 980, 0.5% was added. The mass was mixed until smooth. The twomixtures were combined. Vitamin E, 0.15% and benzethonium chloride, 0.2%were added to the combined mass which was then cooled to ambienttemperature. The mixture was mixed under high shear until a smooth andcreamy product was obtained, a moisturizing salve containing 20% oliveoil.

Example 15

Example 14 was repeated but for the addition of TEA in a concentrationequal to 0.1 mole % of the stearic acid constituent which was added tothe distilled water in the first mass. In accordance with the presentinvention this addition converts the DDAS, formed in the first step ofExample 14, into distearyl stearamide (DSS).

Testing of the Products of Examples 14 and 15

The moisturizer products of Example 14 and 15 were each heated to 170°C. for 30 minutes in a convection oven. They were each allowed to coolin the closed oven for 2 hours. Free oil obtained in each sample wascollected and weighed and the concentration of free oil determined. Nofree oil was obtained from either sample although the sample of Example15 evidenced visible surface oil.

This test evidences the exceptional stability of both moisturizersalbeit establishing a slight superiority of the moisturizer of Example15.

Example 16

Distilled water (1000 g) was mixed with DDAC (19 g), stearic acid (8.9g), cetyl alcohol (31 g) and glycerol monolaurtate (23.5 g) at 70° C.for 1 hour. Thereupon, TEA (2 g) was added. Gas evolved after 10 minutesat the same 70° C. temperature. The product of this example wasreplicated but for the replacement of TEA with an equimolar amount oftriethanolamine stearate (TEA Stearate). The resultant gas evolution isidentical to that noticed when TEA was added.

Analysis of Example 16

This establishes that organic bases such that TEA are equally effectivein the salt form as the unprotonated form of to make the amide productfrom the quaternary compound proceeds to completion.

Examples 17-24

The following examples, summarized in tabular form in Table 5,illustrate various transdermal compositions. The amounts in Table 5 areweight % of the final product. In the following examples, some of thecomponents have a subscript, such as TEA₁, TEA₂, etc. The subscriptexemplifies the first addition of the component to the mixtures. Thus,TEA₁ signifies the first addition of TEA to the mixture, while TEA₂signifies the second addition of TEA to the reaction mixture. Theexamples also indicates the reaction conditions. The added componentsand the products are indicated in the following table.

In Table 6, identified products prepared or left unreacted in eachexample, based on the reaction conditions, such as DDAC, distearylstearamide, dimethyl distearyl ammonium stearate, cetyl stearate,triethanolamine stearate and the like, are indicated. The products aregiven as a mole ratio of product relative to stearic acid. Thus, anyproduct present in greater amounts than stearic acid has a mole ratiogreater than 1.

TABLE 5 Summary of: Ex. 21 Ex. 22 Composition Ex. 17 Ex. 18 Ex. 19 Ex.20 Deep Subcutaneous Ex. 23 Ex. 24 use Blister Bug Bite Bed Sore MinorCut Wound Bruise Diaper Antiseptic Ingredient healing formula HealingFormula granulation Healing Rash Handwash Acid Reaction Zone Water₁ 36.912.28 38.3 38.2 28.49 52.43 47.0 38.5 Symphytum .025 0 0 0 0 0 0 0 AloeVera₁ 0 0 0 .08 .4 0 0 0 TEA₁ .084 0 .084 0 0 .039 .016 0.015 DDAC₁ 3.60 3.6 3.68 3.6 1.94 .44 .414 Stearic acid 4.1 4.1 4.1 4.1 4.1 .89 3.753.525 Cetyl alcohol₁ 3.82 3.82 3.82 3.82 3.82 3.05 0 0 Glycerol mono3.64 0 1.96 0 0 3.45 0 0 stearate Stir @>70 C. until pH is stable TEA₂.084 0 .084 0 0 .039 .016 0.015 Stir @>70 C. until gas evolution iscomplete (about 10 minutes) TEA₃ 1.55 .73 1.52 1.6 1.55 .39 .09 .08 Stir@ >70 C. until smooth & creamy Water₂ 6 30 6 6 6 2 6 6 Aloe Vera₂ .25 .5.1 .02 .1 .25 0 0 DDAC₂ .9 4.5 0.9 .9 .9 0 .87 .81 Mix separately untilDDAC melts; set aside Colostrum .20 .2 .2 .25 .75 0 0 0 Arginine .25 .25.25 .25 .4 0 0 0 L-glutamine .1 0 0 0 .3 0 0 0 Glycine .1 0 0 0 0 0 0 0PCA .1 .2 .2 .2 .1 0 .1 .094 Zinc sulfate .1 .2 .2 .2 0 0 0 0 Proline .1.1 .1 .1 .2 0 0 0 Betaine .1 0 0 0 0 0 0 0 Zinc .1 0 0 0 .3 0 0 0Monomethione Bioperine .08 .08 .08 .08 .1 0 0 0 Ferulic acid .08 .05 .05.05 .1 0 0 0 Lipoec acid .08 .05 .05 .05 .1 0 0 0 Silica gel .05 .1 .1.1 .15 0 0 0 Tetra sodium 1.25 1.5 .75 .75 .75 0 .3 .282 EDTA MSM₁ .845.57 .192 .192 .619 1.0 0 0 Benzethonium .2 .2 .2 .2 .2 .2 .5 .5 chlorideDexpanthenol .63 .33 .33 .33 .33 0 0 0 Phytantriol .315 .11 .11 .11 .110 0 0 Tween-80 .3 .1 .1 .1 0 0 0 0 Grape seed .2 0 .1 .2 .1 0 0 0extract Boswellin 0 .15 .15 .15 0 0 0 0 Berberine HCl 0 .05 .05 .05 0 00 .012 Bilberry 0 0 0 0 .3 0 0 0 Glucosamine 0 0 0 0 .25 0 0 0 HCl RNA 00 0 0 .2 0 0 0 Bee Pollen 0 0 0 0 .1 0 0 0 OKG 0 0 0 0 .1 0 0 0Cu-Curcumin 0 0 0 0 .075 0 0 0 Glycyrrhisic 0 0 0 0 .05 0 0 0 acid Honey0 0 0 0 .2 0 0 0 Povidone 0 0 0 0 0 0 .75 .75 Goldenseal 0 0 0 0 0 0 .150 Triton X-100 0 0 0 0 0 0 2.5 2.35 Dimethicone 0 0 0 0 0 0 2.3 2.162Nonoxynol-9 0 0 0 0 0 0 2.0 1.88 Merquat 550 0 0 0 0 0 0 1.15 1.081Crude beeswax .9 .9 .9 .9 .6 0 1.0 .94 Pregnenolone .2 .2 .2 .2 .2 0 0 0Ascorbyl .15 .15 .15 .15 .2 0 .15 .141 palmitate DHEA .1 .1 .1 .1 .1 0 00 Shark oil 1.6 2.0 2.0 2.0 1.555 0 0 0 Borage oil-23% .5 .432 .432 .432.42 0 0 0 EPA .5 .5 .5 .5 .5 0 0 0 CLA .5 .5 .5 .5 .42 0 0 0 Neem oil.407 .3 .3 .3 .526 0 0 0 Lemon oil .2 .4 .4 .4 .2 0 .5 .47 Jojoba oil 00 0 0 .25 0 0 0 Olive oil 0 0 0 0 0 5.3 0 0 Propolis .3 .3 .3 .3 .25 0.4 .376 Cetyl Alcohol₂ 0 0 0 0 0 0 2.68 2.53 Glycerol mono 0.4 3.7 1.743.7 3.6 0 3.48 3.27 stearate Add, in order Mix until @ >70 C.; Addsmooth DDAC & aloe premix; TEA₄ 3.78 4.17 3.27 3.30 7.65 2.26 2.84 2.04Mix until smooth Propylene glycol 4.0 3.5 3.5 3.5 4.0 1.5 3.5 3.29Glycerin .3 .3 .3 .3 .3 3.5 0 0 Carbomer .5 .475 .5 .5 .3 .75 .35 .752Beta carotene .016 .013 .013 .013 .34 0 0 0 Add Process Increase Aidsand beta shear rate carotene as as mix mix cools to thickens <70 C.Water₃ Add This Add quench quantity quantity water @ sufficient ≧24%temp = 64 C. to = 100 This quench under shear (tip speed >60 in/sec),causes micro crystals to form Lidocaine 2.0 2.0 1.0 1.0 2.0 0 0 0Allantoin .5 .15 .15 .15 .4 .4 .8 .5 MSM₂ .155 .192 .57 .57 .381 0 0 0Vitamin A .002 .002 .002 .002 .06 0 .002 0 Vitamin K .002 .002 .002 .002.006 0 .002 0 Vitamin D .002 .0001 .001 .0001 .006 0 .0001 0 Vitamin E.15 .15 .15 .15 .25 .15 0 0 Lycopene-6% .1 0 0 0 1.104 (12%) 0 0 0Tocotrienol .08 .08 .08 .08 .08 0 0 0 Vanilla .05 .06 .06 .06 .05 .1 0 0Gotu kola 0 0 0 0 .1 0 0 0 Completech 0 0 0 0 .1 0 0 0 Forskoli 0 0 0 0.006 0 0 0 Escin 0 0 0 0 .006 0 0 0 CHG 0 0 0 0 0 0 2.55 1.275 Vit. Eacetate 0 0 0 0 0 0 .25 .235 Merquard 1200 0 0 0 0 0 0 .125 .125Triclosan 0 0 0 0 0 0 .6 0 Povidone iodine 0 0 0 0 0 0 0 6.00 Cool toambient without mixing Ascorbic acid 0 0 0 0 .479 .096 0 0 Mineral oil 00 0 0 0 .85 0 0 Mix @ high shear until creamy & smooth

TABLE 6 PRODUCTS UNDER REACTION CONDITIONS OF EXAMPLES 17-24, EXPRESSEDAS MOLE %/MOLE % STEARIC ACID Product Ex. 17 Ex. 18 Ex. 19 Ex. 20 Ex. 21Ex. 22 Ex. 23 Ex. 24 DDAC 10.1 50.5 10.1 10.1 10.1 0 9.7 9.1 Distearyl40.4 0 40.4 0 0 21.8 4.9 4.6 stearamide Dimethyl 0 0 0 40.4 40.4 0 0distearyl ammonium stearate Cetyl glycerol 91 0 49.5 0 0 87.2 0 0laurate Cetyl Stearate 18.1 100.0 59.6 59.6 59.6 0 0 0 Triethanolamine41.5 0 0 0 0 0 86.6 81.4 stearate Glycerol laurate 10.1 93.5 44 93.5 910 87.9 82.6 Cetyl alcohol 0 9.1 0 49.5 49.5 0 76.7 72.3

Examples 25-28

Examples 25-28 teach how to make aromatic and alehatic tertiary amideswith saturated and unsaturated fatty acids. In each of Examples 25-28, aquaternary surfactant is added to a fatty acid at a time and temperaturesufficient to drive the reaction to completion. As taught above, theconversion to the tertiary amide is a multi-step process. The first stepcreates a gel; the second step breaks the gel and releases a gas. Thesetwo steps iterate back and forth; gel; no gel; gas release; gel; no gel;gas released; and so forth. If the gel is too thick, however, thereaction stops before complete conversion, but the mixture is phasestable and can be transported. Skilled artisans will recognize that morediluent mixture will not visibly gel and more concentrated mixture willvisibly gel.

Example 25

A 4 quart double boiler was stirred with an Admix, Inc., Londonderry,N.H., RS 29 Optishear 200 Rotosolver™ mixer at 1,000 rpm, 4.5 gams TEA,1,960 grams distilled water and 112 grams CLA (conjugated linoleic acid)were mixed and heated to about 80° C.

175 grams of benzethonium chloride was added in 7 steps at 44 grams per15 minutes. After the last benzethonium chloride addition heating wascontinued at 80° C. for 40 minutes, or until gas release was completed.The net weight of the mixture at the end of Example 25 was 1,812 grams.The released gas smells like methanol. The initial gas release wasrapid.

CLA is a floating-on-water fatty acid, liquid at room temperature.Benzethonium chloride is a white powder. The finished product was amilky white, gas-entrained fluid. When analyzed by the USP method forbenzethonium chloride, [CPM Laboratory, Inc., Farmers Branch, Tex.;Method CPM 070] the stoichiometric amount of benzethonium chloride wasrecovered.

The product of Example 25 rubbed into the skin completely in about 15seconds. It was not sticky; it was an opaque gel. The neat gel has astrong, characteristic-unsaturated-fat odor. After rubbing Example 25gel into the skin, there is only a faint residual odor on the skin. Itis theorized that the unsaturated bonds have penetrated the SC while thearomatic branches have not penetrated the SC.

The Example 25 product is benzethonium linoleamide (BLA).

Example 26

Using the apparatus in Example 25, 1,200 grams distilled water, 57 gramsCLA, and 5.5 grams TEA were mixed together and the mixture was heated to80° C., 120 grams dimethyl distearyl ammonium chloride was added at arate of 20 grams/10 minutes. After the last dimethyl distearyl ammoniumchloride addition, heating was continued at 80 C for 10 minutes or untilthe gas release was complete. The gas release in Experiment 26 was slow.“Pinprick” bubbles would be seen percolating to the top of the reactionfluid. The weight of the mixture at the end of Example 26 was 991 grams.

The cooled product of Example 26 was a white precipitate. The Example 26precipitate rubs into the skin in about 20 seconds. There is no residualodor on the skin. The skin has an obvious coating on it with a perceivedcoefficient of friction greater than the untreated skin.

The Example 26 product is distearyl linoleamide (DSL).

Example 27

Using the Example 25 apparatus, 1,200 grams distilled water, 53 gramsstearic acid and 1.1 grams TEA were heated to 80° C. 84 grams ofbenzethonium chloride was added, stepwise at a rate of 14 grams/10minutes. After the last benzethonium chloride addition, heating wascontinued at 80° C. for 20 minutes or until the gas release was complete(the fluid remains full of gas, but gas is not released from thesurface). The weight of the mixture at the end of Example 27 was 929grams.

The cooled product of Example 27 was a white, gaseous fluid. The Example27 product rubs into the skin in about 15 seconds. There is no odor andthe product is not perceived on the skin.

The Example 27 product is benzethonium stearamide (BSA).

Example 28

Using the Example 25 apparatus, 1,200 grams distilled water, 53 gramsstearic acid and 5.5 gams TEA was heated to 80° C. 115 grams dimethyldistearyl ammonium chloride was added, stepwise, at 19 grams/10 minutes.Heating was continued at 80 C for 10 minutes or until the gas releasewas complete. The weight of the mixture at the end of Example 2.8 was988 grams.

The Cooled product of Example 28 was a greasy white solid. The Example28 product rubs into the skin in about 20 seconds. There was no odor.The skin has a readily perceived dry coating after rub-in.

The Example 28 product was distearyl stearamide (DSS).

Example 29

Example 29 illustrates intentionally incomplete conversion withunsaturated fatty acids.

Using the Example 25 apparatus, except the stirring rate was 2,000 rpm,960 grams distilled water, 1.2 grams TEA, 112 grams CLA was heated to80° C. 32 grains benzethonium chloride was added thereto. Agitatedheating was continued at 80 C for 25 minutes. 63 grams borage oil wasadded thereto. Borage oil is an unsaturated fatty acid with about 23%C_(18:3); the rest of borage oil is largely C_(18:2). 8 grams ofadditional TEA and 323 grams dimethyl distearyl ammonium chloride wereadded. The agitated heating was continued for an additional 50 minutesat 80 C.

The Example 29 mixture was allowed to cool to ambient temperature. Thefinal weight was 1,094 g. Example 29 is sufficiently phase stable to beadded at a later time to Example 30 without additional mixing. Theconversion of the quaternary surfactants and fatty acids to tertiaryamides are intentionally incomplete such that a meta stable grease isformed that can be stored and transported for later use as a premix.

Example 29 contains BLA and DSL.

Example 30

In Example 30, the Example 29 unsaturated premix was diluted with waterto allow the no gel step to occur and the reaction to go to completion.The product was made into a finished product.

Example 30 is a wound care product designed to induce granulation inchronic wounds that require skin granulation to heal completely.

9,365 grams of distilled water was heated with 656 grains stearic acidand 243 grams of dimethyl distearyl ammonium chloride to 70 C for 15minutes in a 5 gallon round bottom mixing kettle with an AdmixRotosolver agitator (2.84 inch diameter) at 300 rpm. 611 grams cetylalcohol was added to the water mixture and heated for 35 minutes at70-80° C., 120 g EDTA, 120 g colostrum, 108 g MSM, 64 g arginine, 48 gL-glutamine, 48 g bilberry, 48 g L-opti zinc, 40 g glucosamine, 32 gproline, 32 g RNA, 24 g silica gel, 16 g bee pollen, 16 g ornithineketoglutarate (hereinafter “OKG”), 16 g bioperine, 16 g ferulic acid, 16g lipoec acid, 12 g Cu-curcumin, 8 g glycrrhizic acid, 53 gdexpanthenol, 32 g honey, 18 g phytantriol, 256 g shark oil, 64 g neemoil, 64 g eicosapentaenoic acid (hereinafter “EPA”), 40 g jojoba oil and32 g lemon oil were added and heated at 70-80 C for 5 minutes at amixing rate of 350 rpm.

51 g TEA was added. The mixture was heated for 5 minutes at 70-80° C.1.43 g of dimethyl distearyl ammonium chloride, 80 g aloe vera, 16 ggrape seed extract and 1,413 g TEA were added. The mixture was heatedfor 5 minutes at 70-80° C.

576 g Lauricidin, 96 g beeswax, 32 g pregnenolone, 32 g ascorbylpalmitate and 16 g DHEA were added thereto and the ingredients weremixed together for 5 minutes at 70-80° C. The Example 29 premix (1,094g) was added. The agitator speed was increased to 450 rpm. The mixturewas allowed to cool. Then 4 g of propolis was added at 71° C., 640 gpropylene glycol and 48 g glycerin at 70° C. was added thereto. 48 gCarbomer 980 NF at 68° C. was added. At 65° C., 54 g 95% beta carotenewas added and agitation was increased to 600 rpm.

At 62° C., agitation was increased to 1,000 rpm. At 56 C, agitation wasincreased to 1,300 rpm. At 55° C., 320 g lidocaine was added, 64 gallantoin, 52 g MSM, 16 g Gotu Kola, 1 g of escin, 1 g of forskoli, 1 geach of Vitamins A, D, K, 320 g 6% lycopene, 40 g Vitamin E and 13 gtocotrienol were added to the mixture and the contents were mixed for 2minutes.

It was cooled to ambient temperature, and 82 g rams ascorbic acid wasadded at an agitation speed of 2,850 rpm and mixed for 3 minutes.

Example 30 product was applied to chronic, deep, diabetic foot ulcersthat had not healed in 1-3 years. All treated ulcers were completelyhealed within 60-90 days after treatment.

Example 31

The example illustrates an intentionally incomplete conversion withsaturated fatty acids.

In a 5 gallon round-bottomed cooking kettle with a centered, AdmixRotosolver agitator (2,84″ diameter), 12,525 g distilled water washeated with 88 g TEA, 1,673 g stearic acid and 1,320 g benzethoniumchloride to 80 C at 350 rpm for 20 minutes.

1,817 g dimethyl distearyl ammonium chloride was added thereto and themixture was heated 10 additional minutes at 80° C. The net weight was17,000 g.

Example 31 is an intentionally incomplete reaction. Example 31 is ameta-phase stable semi-solid premix that can be stored, transported andused without remixing.

Example 32

in Example 32, the Example 31 saturated premix is diluted with Water tocomplete the reaction and then made into a more neutral pH finishedproduct.

In a 20 gallon round-bottomed kettle with an off-center Admix Rotosolveragitator (2.84″ diameter), 29,554 g distilled water was heated with2,132 g stearic acid and 3,950 g of the Example 31 product to 80° C. for10 minutes at 600 rpm. The mix released a large amount of gas as theExample 31 reactions go to completion in the diluted, visibly-gel-freeenvironment of Example 32.

1,771 g of cetyl alcohol was added and heated at 70-80° C. for 50minutes. Cetyl stearate was formed in this step.

495 g povidone, 198 g EDTA, 660 PCA, 10 g goldenseal, 70 g TEA and 569 gdimethyl distearyl ammonium chloride were added and mixed at 750 rpm for5 minutes at 70-80° C.

1,863 g TEA, 2,293 g Lauricidin, 660 g beeswax, 99 g ascorbyl palmitate,1,650 g Triton X-100, 1.5 18 g dimethicone, 1,320 g nonoxynol-9, 759 gMerquat 550 and 330 g lemon oil were added. The speed was increased to1,300 rpm and mixed 5 minutes at 70-80° C. The heat was turned off.

265 g propolis at 71° C. was added. The mixture was 2,310 g propyleneglycol was added at 70° C. 265 g Carbomer 940NF was next added at 68° C.

At 65 C, agitation was increased to 1,600 rpm. At 60 C, agitation wasincreased to 2,000 rpm and 11,418 g distilled water was added thereto.

At 55° C. or less, the speed was increased to 3,000 rpm. 165 g Vitamin Eacetate, 83 g Merguard 1200, 264 g allantoin, L3 g Vitamin A, 0.07 gVitamin D, 396 g triclosan and 4,422 g chlorhexidine gluconate (CHG)solution was added and mixed 2 minutes.

Cool to ambient in 5 gallon covered pails. Each pail was mixed for 3minutes at 2,850 rpm. The yield is 66,000 g.

Example 32 product is an anti-bacterial skin protectant. It isnon-irritating, non sticky and moisturizes the skin, it providespersistent antibacterial protection for up to 6 hours. The pH of Example32 increases as it cools. The ambient pH is 7.3. Example 32 product isstable for 2 years.

Example 33

In this example the Example 31 saturated premix was made into an acid pHfinished product.

Example 33 is a persistent antiseptic skin protectant made with theExample 31 premix. Example 33 contains povidone iodine. Povidone iodineis normally not stable at pH>4.5.

In the apparatus of Example 32, 30,272 g distilled water was mixed with2,057 g stearic acid and 4,249 g of Example 31 saturated premix for 10minutes at 70-80 C at 350 rpm. Gas was released as the Example 31reactions went to completion. 1,771 g cetyl alcohol was added theretoand the mixture was heated for 50 minutes at 7080° C.

495 g povidone, 198 g EDTA, 66 g PCA, 110 g TEA and 404 g dimethyldistearyl ammonium chloride were added and the mixing speed wasincreased to 750 rpm. The mixture was heated 5 minutes at 70-80 C.

534 g TEA, 2,496 g Lauricidin, 660 g beeswax, 1.51 8 g dimethicone,1,650 g Triton X-100, 1,320 Nonoxynol-9 and 792 g Merquat 550 were addedto the mixture. The mixing speed was increased to 1,300 rpm. Then themixture was heated at 70-80° C. for 5 minutes. The heat was turned offand the mixture began cooling.

264 g propolis was added at 71 C.

2,310 g propylene glycol was added at 70 C, 581 g Carbomer 940 NF wasadded at 68 C. At 65° C., the mixing speed was increased to 1,600 rpm.

At 60° C., the mixing speed was increased to 2,000 rpm and 11,418 gdistilled water was added. 99 g Merquard 1200 and 825 g CHG solutionwere added.

The mixture was cooled in 5 gallon pails. At ambient temperature, themixture was whipped 3 minutes at 3,300 rpm. About one day afterwhipping, 4,950 g povidone iodine was added, mixing at 2,850 rpm for oneminute.

The final pH is 4.4. The iodine was stable for at least one year.

Example 33 product not only reduced the microbial counts on the handsone minute after application, it also reduced the counts 6 hours afterapplication, making Example 33 a persistent antiseptic.

The FDA temporary final monograph for Health-Care Antiseptic DrugProducts defines an antiseptic hand wash as “an antiseptic containingpreparation designed for frequent use; it reduces the number oftransient microorganisms on intact skin to an initial base line levelafter adequate washing rinsing and drying. It is broad spectrum, factacting and possible, persistent”. The FDA definition underscores thedifficulty of making an antiseptic persistent.

Example 34

In Example 34 a moisturizing production made with a water extract ofLilium Longiflorum lily root extract. Example 34 illustrates how cetylglycerol laurate (CGL) and distearyl stearamide (DSS) are made in situ.The Example 34 product is useful for treating various types of skincancer.

In the apparatus of Example 32, 20,611 g distilled water were mixed with17.6 g TEA, 874 g dimethyl distearyl ammonium chloride and 402 g stearicacid. The stirring rate was 1,000 rpm. The mixture was heated to 70-80 Cfor 10 minutes. [The conversion to DSS begins, but does not go tocompletion.] 1,374 g cetyl alcohol and 1,553 g Lauricidin (glycerolmonolaurate) were added. The mixture was heated 50 minutes at 70-80 C.[The cetyl alcohol converts to cetyl stearate, then to cetyl glycerollaurate (CGL) and stearic acid. The stearic acid eventually is convertedto DSS.]

An additional 17.6 g TEA was added, to the mixture. The mixture washeated for 10 minutes at 70-80° C. 194 g TEA was added and the mixtureheated for 5 minutes at 7080° C. at 1,300 rpm. 2,385 g olive oil and 90g benzethonium chloride and 833 g TEA were added to the mixture. Theheat was turned off and the reaction mixture was allowed to cool.

675 g propylene glycol and 1,575 g glycerin were added to the mixture at70° C. The stirring speed was increased to 1,600 rpm at 68° C.; 293 gCarbomer 940NF was added to the mixture. At 67° C., stirring wasincreased to 2,000 rpm.

At 66 C, stirring was increased to 2,500 rpm; 14,850 g of lily rootextract was next added to the mixture.

The mixture was cooled to ambient in 5 gallon pails. The mixture wasstirred at 3,300 rpm; add 383 g mineral oil and 90 g vanilla extract.

Example 34 is a moisturizing lotion with an unexpected skin carebenefit. Users with skin cancer were cured. Various other herbalextracts can be substituted for the lily root extract.

Example 35

In Example 35, a moisturizing product made with a water extract ofLilium Longiflorum is made using the premix of Example 31 and a beeswaxocclusive layer instead of the mineral oil occlusive layer used in 34.The Example 31 premix includes BSA and DSS.

In the apparatus of Example 32, 26,117 g of distilled water is mixedwith 3,960 g of Example 31 premix, 172 g stearic acid, 600 g dimethyldistearyl ammonium chloride, 2,047 g cetyl alcohol and 4,293 gLauricidin. The stirring rate was 600 rpm. The mix is heated to 80° C.for 60 minutes. [The premix reactions of to completion and the cetylalcohol and Lauricidin convert to cetyl glycerol laurate.] 703 g TEA wasadded and mixed for 5 minutes at 80° C.

66 g PCA, 660 g MSM and 495 g povidone are added to the mix and stirredfor 5 minutes at 80° C.

1,079 g TEA are added to the mix and stirred at 80° C. at 1,000 rpm for5 minutes.

165 g aloe vera, 660 g beeswax, 264 g lemon oil and 3,300 g olive oilare added to the mix and stirred for 5 minutes at 80° C.

990 g propylene glycol are added at 70° C. 363 g Carbomer 980NF areadded at 68° C.

At 64°, the stirring rate is increased to 1,300 rpm. 21,780 g of ambientwater extract of lily root is added substantially all at once. Thetemperature drops down to less than 55° C. and microspheres are formed.

The stirring rate is increased to 1,600 rpm. 462 g allantoin, 198 g palmtocotrienol, 1.3 g each of Vitamins A, D and K are added to the mix.

The mix is cooled to ambient temperature in 5 gallon pails, then eachpail is stirred at 2,850 rpm for 3 minutes. 63 g of ascorbic acid areadded proportionately to each pail during whipping.

Example 35 is a moisturizing skin protectant with a soft silky feel asopposed to the greasy feel that comes from using mineral oil.

Example 6

Example 36 shows how to make cetyl glycerol laurate (UM).

1,200 g distilled water, 5 g benzethonium chloride, 6 g stearic acid aremixed together in the Example 25 apparatus and stirred at 1,000 rpm andheated to 80° C.

100 g cetyl alcohol and 113 g Lauricidin are added to the mix and heatedfor 75 minutes at 80° C.

5 g benzethonium chloride is added and cooked at 80° C. for 10 minutes.

The Example 36 mixture was allowed to cool to ambient temperature. Thefinal weight was 1,053 g.

The Example 36 mixture rubs into the skin in about 10 seconds. It iswhite grease.

The initial benzethonium chloride and stearic acid lower the pH. Thereis a small molar excess of stearic acid. The cetyl alcohol reacts withthe excess stearic acid and then with the Lauricidin. After 75 minutes,substantially all the cetyl alcohol and all the Lauricidin are reacted.

Benzethonium chloride is added to react with the excess stearic acid.

Example 36 contains a small amount of BSA and a substantial amount ofCCL in water.

Example 37

The composition of Example 20 was replicated except that thebenzethonium chloride was added at a temperature lower than the freezingpoint of stearic acid, i.e., at 55° C.

There was an immediate unexpected increase in the level of mixing vesseland a temperature drop greater than the temperature drop associated withthe sensible heat of adding ambient temperature ingredients.

Analysis of Example 37

Benzethonium chloride reacted with the still-liquid unsaturated fattyacids in the mix to form the tertiary amide and methanol gas.Benzethonium chloride did not react with the stearic acid because thetemperature was below the melting point of stearic acid. Benzethoniumchloride did not react with stearic acid in Example 20 because of thepresence of inhibitors such as aloe Vera.

The gas entrained in the mix accounts for the increased level. Theendothermic temperature drop is seen when tertiary amides form.

The above preferred embodiments and examples are given to illustrate thescope and spirit of the present invention. These embodiments andexamples will make apparent to those skilled in the art otherembodiments and example. These other embodiments are within thecontemplation of the present invention. Therefore, the present inventionshould be limited only by the appended claims.

What is claimed is:
 1. A process for making a hydrate of a tertiaryamide of the formula:

or pharmaceutically acceptable salts thereof, wherein: R₄ is a fattygroup of 11-29 carbon atoms; R₅ and R₆ are independently lower alkyl,aryl, aryl lower alkyl, or fatty group containing 11-29 carbon atoms orR₇; R₇ is R₁—Ar—O—R₂—O—R₃—; R₂ and R₃ are independently alkylene groupscontaining 1-6 carbon atoms; R₁ is a lower alkyl; and Ar is aryl; saidfatty group either being completely saturated or containing 1-8carbon-carbon double bonds; the process comprising: (a) providing amixture comprising (i) an aqueous medium, (ii) a quaternary ammoniumsalt, and (iii) a fatty acid or salt thereof, wherein the quaternaryammonium salt is of the formula

wherein  R₉ and R₁₀ are independently lower alkyl; and  X is acounterion; and the fatty acid contains 12-30 carbon atoms; (b)maintaining the mixture for sufficient time under conditions effectiveto form the tertiary amide, wherein said conditions effective to formthe tertiary amide comprise (i) pH of the mixture less than 4.5; and(ii) temperature of the mixture above the melting point of the fattyacid and below the boiling point of the aqueous medium; and (c) coolingthe mixture to ambient temperature, so that the hydrate is formed. 2.The process of claim 1, wherein the molar ratio of the quaternaryammonium salt to the fatty acid is from about 10:1 to about 1:10.
 3. Theprocess of claim 2, wherein the molar ratio of the quaternary ammoniumsalt to the fatty acid is from about 5:1 to about 1:5.
 4. The process ofclaim 2, wherein the molar ratio of the quaternary ammonium salt to thefatty acid is from about 2:1 to about 1:2.
 5. The process of claim 2,wherein the molar ratio of the quaternary ammonium salt to the fattyacid is about 1:1.
 6. The process of claim 1, wherein said conditionseffective to form the tertiary amide comprise temperature of the mixtureabove 60° C.
 7. The process of claim 1, wherein the mixture furthercomprises (iv) a nitrogenous organic base.
 8. The process of claim 7,wherein the nitrogenous base is present in a molar amount from about 0.2to about 1.0 per mole of quaternary ammonium salt.
 9. The process ofclaim 7, wherein the nitrogenous base is present in a molar amount fromabout 0.3 to about 0.6 per mole of quaternary ammonium salt.
 10. Theprocess of claim 7, wherein the nitrogenous base is present in a molaramount from about 0.16 to about 0.50 per mole of quaternary ammoniumsalt.
 11. The process of claim 7, wherein the nitrogenous base is of theformula H₂N(C₁₋₆ alkyl or C₁₋₆ alkanol), HN(C₁₋₆ alkyl or C₁₋₆ alkanol)₂or N(C₁₋₆ alkyl or C₁₋₆ alkanol)₃, wherein each instance of C₁₋₆ alkylor C₁₋₆ alkanol is independently selected.
 12. The process of claim 7,wherein the nitrogenous base is of the formula N(C₁₋₆alkanol)₃.
 13. Theprocess of claim 7, wherein the nitrogenous base is triethanolamine,trimethanolamine, trimethylamine, triethylamine or tromethamine.
 14. Theprocess of claim 7, wherein the nitrogenous base is triethanolamine. 15.The process of claim 1, wherein X is a halide.
 16. The process of claim1, wherein X is a chloride.
 17. The process of claim 1, wherein: R₅ andR₆ are independently a fatty group containing 11-29 carbon atoms; or oneof R₅ and R₆ is aryl or aryl lower alkyl, and the other is is R₇. 18.The process of claim 1, wherein the quaternary ammonium salt isdistearyl dimethyl ammonium chloride or benzethonium chloride.
 19. Theprocess of claim 1, wherein R₄ contains 15-21 carbon atoms.